Updated on 2022/05/25

写真a

 
YAMAGUCHI, Junichiro
 
Affiliation
Faculty of Science and Engineering, School of Advanced Science and Engineering
Job title
Professor

Concurrent Post

  • Faculty of Science and Engineering   Graduate School of Advanced Science and Engineering

Research Institute

  • 2020
    -
    2022

    理工学術院総合研究所   兼任研究員

Research Experience

  • 2018.04
    -
    Now

    Waseda University   Faculty of Science and Engineering   Professor

  • 2016.04
    -
    2018.03

    Waseda University   Faculty of Science and Engineering   Associate Professor

  • 2012.04
    -
    2016.03

    Nagoya University   Graduate School of Science   Associate Professor

  • 2012.08
    -
    2012.09

    ドイツミュンスター大学客員准教授

  • 2008.08
    -
    2012.03

    名古屋大学理学研究科助教

  • 2007.04
    -
    2008.07

    スクリプス研究所化学科博士研究員

  • 2007.04
    -
    2008.07

    日本学術振興会海外特別研究員

  • 2004.04
    -
    2007.03

    日本学術振興会特別研究員(DC1)

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Professional Memberships

  •  
     
     

    アメリカ化学会

  •  
     
     

    近畿化学協会有機金属部会

  •  
     
     

    有機合成化学協会

  •  
     
     

    日本化学会

  •  
     
     

    American Chemical Society

  •  
     
     

    The Kinki Chemical Society, Japan

  •  
     
     

    The Society of Synthetic Organic Chemistry, Japan

  •  
     
     

    The Chemical Society of Japan

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Research Areas

  • Synthetic organic chemistry

Research Interests

  • 汎用官能基切断型カップリング

Papers

  • Convergent Azaspirocyclization of Bromoarenes with N-Tosylhydrazones by a Palladium Catalyst

    Aika Yanagimoto, Yota Uwabe, Qikun Wu, Kei Muto, Junichiro Yamaguchi

    ACS CATALYSIS   11 ( 16 ) 10429 - 10435  2021.08

     View Summary

    1-Azaspirocyclic compounds have gained attention in chemistry and drug discovery fields. In this manuscript, the development of a Pd-catalyzed dearomative azaspirocyclization of bromoarenes bearing an aminoalkyl group with N-tosylhydrazones is described. The present method enables azaspirocyclization with the introduction of carbon substituents, achieving the convergent synthesis of 1-azaspirocycles. This method allowed furan, thiophene, and naphthalene cores to generate the corresponding 1-azaspirocycles. The obtained azaspirocycles from furans were further elaborated via an acid-catalyzed rearrangement to afford 1-azaspirocyclopentenones.

    DOI

  • Ni-Catalyzed Aryl Sulfide Synthesis through an Aryl Exchange Reaction

    Ryota Isshiki, Miki B. Kurosawa, Kei Muto, Junichiro Yamaguchi

    Journal of the American Chemical Society   143 ( 27 ) 10333 - 10340  2021.07

     View Summary

    A Ni-catalyzed aryl sulfide synthesis through an aryl exchange reaction between aryl sulfides and a variety of aryl electrophiles was developed. By using 2-pyridyl sulfide as a sulfide donor, this reaction achieved the synthesis of aryl sulfides without using odorous and toxic thiols. The use of a Ni/dcypt catalyst capable of cleaving and forming aryl-S bonds was important for the aryl exchange reaction between 2-pyridyl sulfides and aryl electrophiles, which include aromatic esters, arenol derivatives, and aryl halides. Mechanistic studies revealed that Ni/dcypt can simultaneously undergo oxidative additions of aryl sulfides and aromatic esters, followed by ligand exchange between the generated aryl-Ni-SR and aryl-Ni-OAr species to furnish aryl exchanged compounds.

    DOI PubMed

  • Development of Pd-Catalyzed Denitrative Couplings

    Kitty K. Asahara, Myuto Kashihara, Kei Muto, Yoshiaki Nakao, Junichiro Yamaguchi

    JOURNAL OF SYNTHETIC ORGANIC CHEMISTRY JAPAN   79 ( 1 ) 11 - 21  2021.01

     View Summary

    Transition metal-catalyzed cross-coupling between aryl halides and nucleophiles is one of the most reliable C-C and C-heteroatom bond forming reactions. However, preparation of haloarenes usually requires multi-step operation, making the whole cross-coupling process inefficient. Nitroarenes, synthesized by a single-step nitration of arenes, can be attractive alternatives as electrophiles in cross-coupling methodology, but inherent inertness of C(sp(2))-NO2 bonds toward metal catalysts has been a bottleneck of general denitrative transformations. Recently, we have overcome this obstacle and achieved direct activation of Ar-NO2 bonds by using Pd/BrettPhos catalysis. Herein, we describe the development of denitrative couplings by Pd/BrettPhos catalyst and its unique suitability from a mechanistic point of view. Deep understanding of reaction mechanism also enabled us to design more active Pd/NHC system.

  • Transition-Metal-Catalyzed Denitrative Coupling of Nitroarenes

    Kei Muto, Toshimasa Okita, Junichiro Yamaguchi

    ACS Catalysis   10 ( 17 ) 9856 - 9871  2020.09

     View Summary

    Functionalization of arenes is a topic of central importance in diverse fields ranging from medicinal chemistry to materials science. Metal-catalyzed cross-coupling and nucleophilic aromatic substitution are among the most reliable methods to access functionalized arenes. In these reactions, haloarenes are often used as a versatile synthetic platform to introduce various functional groups. However, haloarenes are typically prepared from the corresponding nitroarenes through the classic sequence of reduction, diazotization, and halogenation. Thus, haloarene cross-coupling can become a multistep transformation overall. To avoid this lengthy sequence, the direct utilization of nitroarenes has the potential to significantly streamline synthetic processes and, therefore, has attracted attention in the chemistry community from the vantage points of atom- A nd step-economy. In this Review, we comprehensively cover advances in transition-metal-catalyzed denitrative reactions of nitroarenes.

    DOI

  • Pd-catalyzed C4-Dearomative Allylation of Benzyl Ammoniums with Allyltributylstannane

    Yuki Kayashima, Masaaki Komatsuda, Kei Muto, Junichiro Yamaguchi

    Chemistry Letters   49 ( 7 ) 836 - 839  2020.07  [Refereed]

    DOI

  • Solvent Selection Scheme Using Machine Learning Based on Physicochemical Description of Solvent Molecules: Application to Cyclic Organometallic Reaction

    Mikito Fujinami, Hiroki Maekawara, Ryota Isshiki, Junji Seino, Junichiro Yamaguchi, Hiromi Nakai

    BULLETIN OF THE CHEMICAL SOCIETY OF JAPAN   93 ( 7 ) 841 - 845  2020.07

     View Summary

    A solvent selection scheme for optimization of reactions is proposed using machine learning, based on the numerical descriptions of solvent molecules. Twenty-eight key solvents were represented using 17 physicochemical descriptors. Clustering analysis results implied that the descriptor represents the chemical characteristics of the solvent molecules. During the assessment of an organometallic reaction system, the regression analysis indicated that learning even a small number of experimental results can be useful for identifying solvents that will produce high experimental yields. Observation of the regression coefficients, and both clustering and regression analysis, can be effective when selecting a solvent to be used for an experiment.

    DOI

  • Ester dance reaction on the aromatic ring

    Kaoru Matsushita, Ryosuke Takise, Kei Muto, Junichiro Yamaguchi

    Science Advances   6 ( 28 ) eaba7614 - eaba7614  2020.07  [Refereed]

     View Summary

    Aromatic rearrangement reactions are useful tools in the organic chemist’s toolbox when generating uncommon substitution patterns. However, it is difficult to precisely translocate a functional group in (hetero) arene systems, with the exception of halogen atoms in a halogen dance reaction. Here, we describe an unprecedented “ester dance” reaction: a predictable translocation of an ester group from one carbon atom to another on an aromatic ring. Specifically, a phenyl carboxylate substituent can be shifted from one carbon to an adjacent carbon on a (hetero) aromatic ring under palladium catalysis to often give a thermodynamically favored, regioisomeric product with modest to good conversions. The obtained ester moiety can be further converted to various aromatic derivatives through the use of classic and state-of-the-art transformations including amidation, acylations, and decarbonylative couplings.

    DOI

  • σ-Bond Hydroboration of Cyclopropanes

    Hiroki Kondo, Shin Miyamura, Kaoru Matsushita, Hiroki Kato, Chisa Kobayashi, Arifin, Kenichiro Itami, Daisuke Yokogawa, Junichiro Yamaguchi

    Journal of the American Chemical Society   142 ( 25 ) 11306 - 11313  2020.06

    DOI

  • Dearomative Allylation of Naphthyl Cyanohydrins by Palladium Catalysis: Catalyst-Enhanced Site Selectivity

    Aika Yanagimoto, Masaaki Komatsuda, Kei Muto, Junichiro Yamaguchi

    Organic Letters   22 ( 9 ) 3423 - 3427  2020.05  [Refereed]

    DOI

  • Catalytic Deoxygenative Coupling of Aromatic Esters with Organophosphorus Compounds

    Miki B. Kurosawa, Ryota Isshiki, Kei Muto, Junichiro Yamaguchi

    Journal of the American Chemical Society   142 ( 16 ) 7386 - 7392  2020.04  [Refereed]

    DOI

  • Palladium-Catalyzed Mizoroki–Heck Reaction of Nitroarenes and Styrene Derivatives

    Toshimasa Okita, Kitty K. Asahara, Kei Muto, Junichiro Yamaguchi

    Organic Letters   22 ( 8 ) 3205 - 3208  2020.04  [Refereed]

    DOI

  • Ester Transfer Reaction of Aromatic Esters with Haloarenes and Arenols by a Nickel Catalyst

    Ryota Isshiki, Naomi Inayama, Kei Muto, Junichiro Yamaguchi

    ACS Catalysis   10 ( 5 ) 3490 - 3494  2020.03  [Refereed]

    DOI

  • Decarbonylative Synthesis of Aryl Nitriles from Aromatic Esters and Organocyanides by a Nickel Catalyst

    Keiichiro Iizumi, Miki B. Kurosawa, Ryota Isshiki, Kei Muto, Junichiro Yamaguchi

    Synlett    2020

     View Summary

    A decarbonylative cyanation of aromatic esters with aminoacetonitriles in the presence of a nickel catalyst was developed. The key to this reaction was the use of a thiophene-based diphosphine ligand, dcypt, permitting the synthesis of aryl nitrile without the generation of stoichiometric metal- or halogen-containing chemical wastes. A wide range of aromatic esters, including hetarenes and pharmaceutical molecules, can be converted into aryl nitriles.

    DOI

  • Catalytic three-component C–C bond forming dearomatization of bromoarenes with malonates and diazo compounds

    Hiroki Kato, Itsuki Musha, Masaaki Komatsuda, Kei Muto, Junichiro Yamaguchi

    Chemical Science   11 ( 33 ) 8779 - 8784  2020  [Refereed]

     View Summary

    <p>A catalytic three-component C–C bond forming dearomatization of bromoarenes was developed, enabling rapid access to multi-substituted alicycles.</p>

    DOI

  • Pd-Catalyzed Alkenyl Thioether Synthesis from Thioesters and N-Tosylhydrazones

    Kota Ishitobi, Kei Muto, Junichiro Yamaguchi

    ACS Catalysis   9 ( 12 ) 11685 - 11690  2019.12  [Refereed]

    DOI

  • Asymmetric Synthesis of a 5,7-Fused Ring System Enabled by an Intramolecular Buchner Reaction with Chiral Rhodium Catalyst

    Takayuki Hoshi, Eisuke Ota, Yasuhide Inokuma, Junichiro Yamaguchi

    Organic Letters   21 ( 24 ) 10081 - 10084  2019.12  [Refereed]

    DOI PubMed

  • Structure-function study of a novel inhibitor of the casein kinase 1 family in Arabidopsis thaliana.

    Ami N Saito, Hiromi Matsuo, Keiko Kuwata, Azusa Ono, Toshinori Kinoshita, Junichiro Yamaguchi, Norihito Nakamichi

    Plant direct   3 ( 9 ) e00172  2019.09  [Refereed]  [International journal]

     View Summary

    Casein kinase 1 (CK1) is an evolutionarily conserved protein kinase family among eukaryotes. Studies in non-plants have shown CK1-dependent divergent biological processes, but the collective knowledge regarding the biological roles of plant CK1 lags far behind other members of the Eukarya. One reason for this is that plants have many more genes encoding CK1 than do animals. To accelerate our understanding of the plant CK1 family, a strong CK1 inhibitor that efficiently inhibits multiple members of the CK1 protein family in vivo (i.e., in planta) is required. Here, we report a novel, specific, and effective CK1 inhibitor in Arabidopsis. Using circadian period-lengthening activity as an estimation of the CK1 inhibitor effect in vivo, we performed a structure-activity relationship study of analogues of the CK1 inhibitor PHA767491 (1,5,6,7-tetrahydro-2-(4-pyridinyl)-4H-pyrrolo[3,2-c]pyridin-4-one hydrochloride). A propargyl group at the pyrrole nitrogen atom (AMI-212) or a bromine atom at the pyrrole C3 position (AMI-23) had stronger CK1 inhibitory activity than PHA767491. A hybrid molecule of AMI-212 and AMI-23 (AMI-331) was about 100-fold more inhibitory than the parent molecule PHA767491. Affinity proteomics using an AMI-331 probe showed that the targets of AMI-331 inhibition are mostly CK1 kinases. As such, AMI-331 is a potent and selective CK1 inhibitor that shows promise in the research of CK1 in plants.

    DOI PubMed

  • Casein kinase 1 family regulates PRR5 and TOC1 in the Arabidopsis circadian clock.

    Takahiro N Uehara, Yoshiyuki Mizutani, Keiko Kuwata, Tsuyoshi Hirota, Ayato Sato, Junya Mizoi, Saori Takao, Hiromi Matsuo, Takamasa Suzuki, Shogo Ito, Ami N Saito, Taeko Nishiwaki-Ohkawa, Kazuko Yamaguchi-Shinozaki, Takashi Yoshimura, Steve A Kay, Kenichiro Itami, Toshinori Kinoshita, Junichiro Yamaguchi, Norihito Nakamichi

    Proceedings of the National Academy of Sciences of the United States of America   116 ( 23 ) 11528 - 11536  2019.06  [Refereed]  [International journal]

     View Summary

    The circadian clock provides organisms with the ability to adapt to daily and seasonal cycles. Eukaryotic clocks mostly rely on lineage-specific transcriptional-translational feedback loops (TTFLs). Posttranslational modifications are also crucial for clock functions in fungi and animals, but the posttranslational modifications that affect the plant clock are less understood. Here, using chemical biology strategies, we show that the Arabidopsis CASEIN KINASE 1 LIKE (CKL) family is involved in posttranslational modification in the plant clock. Chemical screening demonstrated that an animal CDC7/CDK9 inhibitor, PHA767491, lengthens the Arabidopsis circadian period. Affinity proteomics using a chemical probe revealed that PHA767491 binds to and inhibits multiple CKL proteins, rather than CDC7/CDK9 homologs. Simultaneous knockdown of Arabidopsis CKL-encoding genes lengthened the circadian period. CKL4 phosphorylated transcriptional repressors PSEUDO-RESPONSE REGULATOR 5 (PRR5) and TIMING OF CAB EXPRESSION 1 (TOC1) in the TTFL. PHA767491 treatment resulted in accumulation of PRR5 and TOC1, accompanied by decreasing expression of PRR5- and TOC1-target genes. A prr5 toc1 double mutant was hyposensitive to PHA767491-induced period lengthening. Together, our results reveal posttranslational modification of transcriptional repressors in plant clock TTFL by CK1 family proteins, which also modulate nonplant circadian clocks.

    DOI PubMed

  • Pd-Catalyzed Denitrative Intramolecular C-H Arylation

    Kitty K. Asahara, Toshimasa Okita, Ami N. Saito, Kei Muto, Yoshiaki Nakao, Junichiro Yamaguchi

    ORGANIC LETTERS   21 ( 12 ) 4721 - 4724  2019.06  [Refereed]

     View Summary

    A Pd-catalyzed intramolecular C-H arylation of nitroarenes has been developed. Nitroarenes bearing tethered aryl groups at the ortho-position can be readily prepared in one step from 2-halonitroarenes by a nucleophilic aromatic substitution (SNAr). Under Pd/BrettPhos catalysis, activations of the C-NO2 bond as well as the C-H bond on arenes generated the corresponding biaryl linkage in moderate to excellent yields.

    DOI

  • Studying Abroad Led to New Friendships and New Research Directions

    Junichiro Yamaguchi

    YAKUGAKU ZASSHI-JOURNAL OF THE PHARMACEUTICAL SOCIETY OF JAPAN   139 ( 2 ) 229 - 233  2019.02

     View Summary

    Ten years ago, in April 2007, I went abroad to study at The Scripps Research Institute (TSRI) in San Diego, USA. As an overseas researcher with the Japan Society for the Promotion of Science (JSPS), I worked with Professor Phil S. Baran (an associate professor at the time), who was a distinguished young researcher in synthetic organic chemistry. Working abroad had been my dream ever since I had decided to work at a university as a researcher. Through my study of organic chemistry, I hoped to spread my wings and explore the world. Fortunately, the research projects at TSRI went well, and a year and a half later, I returned to Japan, to Nagoya University as an assistant professor (under the guidance of Professor Kenichiro Itami). During my time abroad, 1 certainly gained a lot of experience in chemistry, but as 1 look back to 10 years ago, I feel that the personal interactions remain much more important to me. Numerous Japanese researchers who studied overseas around the same period, and many TSRI graduate students I encountered, are currently faculty members at top universities around the world. At this memorable and nostalgic phase of my life, I am sharing here a personal account of the research I conducted and the researchers I met during my stay in San Diego.

  • Cell-based screen identifies a new potent and highly selective CK2 inhibitor for modulation of circadian rhythms and cancer cell growth.

    Oshima T, Niwa Y, Kuwata K, Srivastava A, Hyoda T, Tsuchiya Y, Kumagai M, Tsuyuguchi M, Tamaru T, Sugiyama A, Ono N, Zolboot N, Aikawa Y, Oishi S, Nonami A, Arai F, Hagihara S, Yamaguchi J, Tama F, Kunisaki Y, Yagita K, Ikeda M, Kinoshita T, Kay SA, Itami K, Hirota T

    Science advances   5 ( 1 ) eaau9060  2019.01  [Refereed]  [International journal]

     View Summary

    Compounds targeting the circadian clock have been identified as potential treatments for clock-related diseases, including cancer. Our cell-based phenotypic screen revealed uncharacterized clock-modulating compounds. Through affinity-based target deconvolution, we identified GO289, which strongly lengthened circadian period, as a potent and selective inhibitor of CK2. Phosphoproteomics identified multiple phosphorylation sites inhibited by GO289 on clock proteins, including PER2 S693. Furthermore, GO289 exhibited cell type-dependent inhibition of cancer cell growth that correlated with cellular clock function. The x-ray crystal structure of the CK2α-GO289 complex revealed critical interactions between GO289 and CK2-specific residues and no direct interaction of GO289 with the hinge region that is highly conserved among kinases. The discovery of GO289 provides a direct link between the circadian clock and cancer regulation and reveals unique design principles underlying kinase selectivity.

    DOI PubMed

  • 45 Synthesis of Dragmacidin D via Direct C-H bond Arylation(Oral Presentation)

    Yamaguchi Junichiro, Mandal Debashis, Yamaguchi Atsushi D., Itami Kenichiro

    Symposium on the Chemistry of Natural Products, symposium papers   ( 53 ) 265 - 270  2011.09

     View Summary

    The search for natural products in marine and terrestrial environments has led to the discovery of a number of biologically active bis(indole)alkaloids, which include the bioactive marine natural product family of dragmacidins. Dragmacidin D (1: Figure 1), which is known as a potent inhibitor of serine-threonine protein phosphatases, has also attracted attention as a lead compound for treating Parkinson's, Alzheimer's and Huntington's diseases. Additionally, two structural isomers of this molecule are known, named dragmacidins E (2) and F (3). Prominent structural features of these compounds are two indole-azine bonds and a complex aminoimidazole moiety. To conquer these unique structures and to study their interesting bioactivity, many synthetic organic chemists have been trying to synthesize 1 and its analogues. However, only Stoltz and coworkers have successfully synthesized these molecules (1 and 3) thus far, using the Suzuki-Miyaura cross-coupling reactions as key steps. Palladium-catalyzed cross-coupling reactions of arylmetal compounds with aryl halides are the most reliable method for C-C bond construction in organic synthesis. However, a fair number of steps would be required to utilize this strategy in the synthesis of dragmacidins, since the aromatic coupling partners must be pre-functionalized. Therefore, our group set out to construct 1 in a concise fashion, which features the direct arylation of C-H bonds without pre-functionalization. In conclusion, the total synthesis of dragmacidin D(1) was achieved, including a newly developed direct arylation strategy which involves an oxidative C3-selective indole-azine (N-oxide) C-H/C-H coupling reaction, aβ-selective thiophene-indole C-H/C-X coupling reaction, and an indole-pyrazinone C-H/C-H coupling reaction.

    DOI CiNii

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Misc

  • Pd-Catalyzed Decarbonylative C−H Coupling of Azoles and Aromatic Esters

    Kaoru Matsushita, Ryosuke Takise, Tomoya Hisada, Shin Suzuki, Ryota Isshiki, Kenichiro Itami, Kei Muto, Junichiro Yamaguchi

    Chemistry - An Asian Journal   13   2393 - 2396  2018.09

     View Summary

    © 2018 Wiley-VCH Verlag GmbH &amp; Co. KGaA, Weinheim A decarbonylative C−H coupling of azoles and aromatic esters by palladium catalysis is described. Our previously reported Ni-catalyzed C−H coupling of azoles and aromatic esters has a significant drawback regarding the substrate scope. Herein, we employ palladium catalysis instead of nickel, resulting in a broader substrate scope in terms of azoles and aromatic esters.

    DOI

  • Pd-Catalyzed Dearomative Allylation of Benzyl Phosphates

    Masaaki Komatsuda, Kei Muto, Junichiro Yamaguchi

    Organic Letters   20   4354 - 4357  2018.07

     View Summary

    Copyright © 2018 American Chemical Society. Dearomative C-C bond formation of benzyl phosphates has been developed. In the presence of a palladium/PAr3catalyst, benzyl phosphates reacted with allyl borates to generate the allylated product in a dearomative fashion. The resulting dearomatized molecules were successfully derivatized by Simmons-Smith cyclopropanation and oxidation.

    DOI

  • Dibenzofuran Synthesis: Decarbonylative Intramolecular C−H Arylation of Aromatic Esters

    Toshimasa Okita, Masaaki Komatsuda, Ami N. Saito, Tomoya Hisada, Tomoaki T. Takahara, Keito P. Nakayama, Ryota Isshiki, Ryosuke Takise, Kei Muto, Junichiro Yamaguchi

    Asian Journal of Organic Chemistry   7   1358 - 1361  2018.07

     View Summary

    © 2018 Wiley-VCH Verlag GmbH &amp; Co. KGaA, Weinheim A method to provide dibenzofurans through decarbonylative C−H arylation is described. Diaryl ethers bearing an ester functional group, which can be readily prepared by a SNAr reaction, underwent intramolecular C−H arylation in the presence of a palladium catalyst to afford the corresponding dibenzofurans. Electron-rich bis(dialkylphosphine)s such as dcype were critical as the ligand, otherwise the reactions did not proceed at all. This is the first example of C−H arylation of aromatic esters with simple arenes utilized in intramolecular fashion.

    DOI

  • Decarbonylative Methylation of Aromatic Esters by a Nickel Catalyst

    Toshimasa Okita, Kei Muto, Junichiro Yamaguchi

    Organic Letters   20 ( 10 ) 3132 - 3135  2018.05

     View Summary

    A Ni-catalyzed decarbonylative methylation of aromatic esters was achieved using methylaluminums as methylating agents. Dimethylaluminum chlorides uniquely worked as the methyl source. Because of the Lewis acidity of aluminum reagents, less reactive alkyl esters could also undergo the present methylation. By controlling the Lewis acidity of aluminum reagents, a chemoselective decarbonylative cross-coupling between alkyl esters and phenyl esters was successful.

    DOI

  • Decarbonylative C-P bond formation using aromatic esters and organophosphorus compounds

    Ryota Isshiki, Kei Muto, Junichiro Yamaguchi

    Organic Letters   20 ( 4 ) 1150 - 1153  2018.02

     View Summary

    Ni-catalyzed C-P bond formation was achieved using aromatic esters as unconventional aryl sources. The key to success was the use of a thiophene-based diphosphine ligand (dcypt). Several aromatic esters including heteroaromatics can be coupled with phosphine oxides and phosphates, providing aryl phosphorus compounds. The synthetic utility of the method was demonstrated by application of the present protocol to the sequential coupling reactions.

    DOI

  • Design, synthesis and evaluation of γ-turn mimetics as LSD1-selective inhibitors

    Yosuke Ota, Shin Miyamura, Misaho Araki, Yukihiro Itoh, Shusuke Yasuda, Mitsuharu Masuda, Tomoyuki Taniguchi, Yoshihiro Sowa, Toshiyuki Sakai, Kenichiro Itami, Junichiro Yamaguchi, Takayoshi Suzuki

    Bioorganic and Medicinal Chemistry   26 ( 3 ) 775 - 785  2018.02

     View Summary

    © 2018 Elsevier Ltd Lysine-specific demethylase 1 (LSD1) is an attractive molecular target for cancer therapy. We have previously reported potent LSD1-selective inhibitors (i.e., NCD18, NCD38, and their analogs) consisting of trans-2-phenylcyclopropylamine (PCPA) or trans-2-arylcyclopropylamine (ACPA) and a lysine moiety that could form a γ-turn structure in the active site of LSD1. Herein we report the design, synthesis and evaluation of γ-turn mimetic compounds for further improvement of LSD1 inhibitory activity and anticancer activity. Among a series of γ-turn mimetic compounds synthesized by a Mitsunobu-reaction-based amination strategy, we identified 1n as a potent and selective LSD1 inhibitor. Compound 1n induced cell cycle arrest and apoptosis through histone methylation in human lung cancer cells. The γ-turn mimetics approach should offer new insights into drug design for LSD1-selective inhibitors.

    DOI PubMed

  • Decarbonylative aryl thioether synthesis by Ni catalysis

    Kota Ishitobi, Ryota Isshiki, Kitty Asahara, Cassandra Lim, Kei Muto, Junichiro Yamaguchi

    Chemistry Letters   47 ( 6 ) 756 - 759  2018

     View Summary

    A decarbonylative aryl thioether synthesis by nickel catalysis is described. After optimization of the reaction conditions, two air-stable Ni catalytic systems [Ni(OAc)2/PnBu3 and Ni(OAc)2/dppb] were identified. Using these catalysts, various aryl thioesters can be converted to the corresponding aryl thioethers in decarbonylative fashion.

    DOI

  • Synthesis of fully arylated (hetero) arenes by coupling reaction

    Takashi Asako, Kei Muto, Junichiro Yamaguchi

    Yuki Gosei Kagaku Kyokaishi/Journal of Synthetic Organic Chemistry   76   98 - 110  2018.01

     View Summary

    Multiply arylated (hetero) arenes are intriguing structural motifs in functional molecules, such as natural products, pharmaceuticals and functional organic materials. In recent decades, many synthesis methods of multiply arylated (hetero) arenes have been reported. As a subclass of multiply arylated arenes, fully arylated (hetero) arenes have also flourished as a unique structural class in functional organic materials and biologically active compounds. Despite the successful application of fully arylated (hetero) arenes with different aryl substituents, the synthesis of such (hetero) arenes has not been explored compared to partially arylated arenes due to the difficulty of synthesizing sterically hindered and highly unsymmetrical aromatic cores. This review reports the synthesis of fully arylated (hetero) arenes bearing more than two different aryl substituents and categorizes this emerging topic by the type of (hetero) arene core, focusing on the methods employing cross-coupling reaction including direct C-H arylation.

    DOI

  • Decarbonylative coupling reaction of aromatic esters

    Ryota Isshiki, Toshimasa Okita, Kei Muto, Junichiro Yamaguchi

    Yuki Gosei Kagaku Kyokaishi/Journal of Synthetic Organic Chemistry   76 ( 4 ) 300 - 314  2018

    Book review, literature introduction, etc.  

     View Summary

    Transition metal-catalyzed cross-coupling reactions are a powerful method to form chemical bonds. Conventionally, haloarenes has been used as the most reliable aryl electrophiles in cross- coupling. Recent studies in the cross-coupling arena have enabled to employ unconventional but ubiquitous aryl electrophiles such as phenol and aniline. With this trend of organic synthesis, cross-coupling reactions using aromatic carboxylic acid derivatives such as esters as aryl electrophiles have gained considerable attention as a de novo and efficient method to construct C-C and C-heteroatom bonds. In order to realize this particular transformation, it is important to develop and design transition metal catalysts, those are active toward the scission of ester C-O bonds and decarbonylation. In this review, we describe the progress of catalytic decarbonylative cross- coupling of aromatic esters including chronological aspects and mechanistic considerations.

    DOI

  • Modular synthesis of heptaarylindole

    Shin Suzuki, Takashi Asako, Kenichiro Itami, Junichiro Yamaguchi

    Organic and Biomolecular Chemistry   16 ( 20 ) 3771 - 3776  2018

     View Summary

    The first synthesis of heptaarylindole (HAI) has been accomplished using a coupling/ring transformation strategy. Four readily prepared modular units (diarylthiophenes, 2-arylaziridines, arylboronic acids, and arylalkynes) were joined together to provide key ynamide intermediates. Subsequent inverse electron-demand intramolecular [4 + 2] cycloaddition furnished pentaarylindoles (PAIs) regioselectively. This strategy was also applied to the synthesis of tetraarylazaindole with four different aryl substituents. PAIs underwent further arylations at the C2- and N1-positions, providing HAI with seven different aryl substituents with virtually complete regioselectivity.

    DOI

  • Natural product synthesis: 30 years later

    Junichiro Yamaguchi

    Yuki Gosei Kagaku Kyokaishi/Journal of Synthetic Organic Chemistry   76 ( 5 ) 510 - 513  2018

     View Summary

    In 2048, the vast majority of occupations have been replaced by artificial intelligence ( AI), we do not do the routine work anymore. In the research of natural product synthesis, it is scenery completely different from the research environment 30 years ago. Here, I anticipate how the synthesis of natural products changed in 30 years.

    DOI

  • Synthesis of a heptaarylisoquinoline: Unusual disconnection for constructing isoquinoline frameworks

    Takashi Asako, Shin Suzuki, Kenichiro Itami, Kei Muto, Junichiro Yamaguchi

    Chemistry Letters   47   968 - 970  2018.01

     View Summary

    © 2018 The Chemical Society of Japan. In a novel disconnection of isoquinoline ring synthesis at the C7C8/C4aC8a bonds, these bonds can be formed by a [4+2] cycloaddition between thiophene S,S-dioxide and alkynes. With a subsequent CH arylation of the resulting hexaarylisoquinoline at the C3 position, the synthesis of a fully substituted isoquinoline has been achieved.

    DOI

  • Catalytic alpha-Arylation of Ketones with Heteroaromatic Esters

    Ryota Isshiki, Ryosuke Takise, Kenichiro Itami, Kei Muto, Junichiro Yamaguchi

    SYNLETT   28 ( 19 ) 2599 - 2603  2017.12

     View Summary

    Heteroaromatic esters were found to be applicable as an arylating agent for the Pd-catalyzed -arylation of ketones in a decarbonylative fashion. The use of our in-house ligand, dcypt, enabled this unique bond formation. Considering the ubiquity and low cost of aromatic esters, the present work will allow for rapid access to valuable -aryl carbonyl compounds.

    DOI

  • Synthesis of Octaaryl Naphthalenes and Anthracenes with Different Substituents

    Shin Suzuki, Kenichiro Itami, Junichiro Yamaguchi

    ANGEWANDTE CHEMIE-INTERNATIONAL EDITION   56 ( 47 ) 15010 - 15013  2017.11

     View Summary

    A synthesis of multiply arylated naphthalenes and anthracenes with eight different substituents has been accomplished. The key intermediates are tetraarylthiophene S-oxides, which are synthesized through a method involving sequential C H arylation and cross-coupling from 3-methoxythiophene, followed by oxidation of the sulfur atom. The resulting tetraarylthiophene S-oxides can be converted into a tetraaryl benzynes or naphthalynes and then merged through [4+2] cycloaddition reaction with another tetraarylthiophene S-oxide, thereby resulting in the programmed synthesis of octaarylnaphthalenes and octaarylanthracenes.

    DOI

  • Cross-coupling of aromatic esters and amides

    Ryosuke Takise, Kei Muto, Junichiro Yamaguchi

    CHEMICAL SOCIETY REVIEWS   46 ( 19 ) 5864 - 5888  2017.10

    Book review, literature introduction, etc.  

     View Summary

    Catalytic cross-coupling reactions of aromatic esters and amides have recently gained considerable attention from synthetic chemists as de novo and efficient synthetic methods to form C-C and C-heteroatom bonds. Esters and amides can be used as diversifiable groups in metal-catalyzed cross-coupling: in a decarbonylative manner, they can be utilized as leaving groups, whereas in a non-decarbonylative manner, they can form ketone derivatives. In this review, recent advances of this research topic are discussed.

    DOI

  • Thiazole-Based sigma(1) Receptor Ligands: Diversity by Late-Stage C-H Arylation of Thiazoles, Structure-Affinity and Selectivity Relationships, and Molecular Interactions

    Artur K. Kokornaczyk, Dirk Schepmann, Junichiro Yamaguchi, Kenichiro Itami, Erik Laurini, Maurizio Fermeglia, Sabrina Pricl, Bernhard Wuensch

    CHEMMEDCHEM   12 ( 13 ) 1070 - 1080  2017.07

     View Summary

    Spirocyclic thiophene derivatives represent promising sigma(1) ligands with high sigma(1) affinity and selectivity over the sigma(2) subtype. To increase ligand efficiency, the thiophene ring was replaced bioisosterically by a thiazole ring, and the pyran ring was opened. Late-stage diversification by regioselective C-H arylation of thiazoles 9a-c resulted in a set of 53 compounds with high diversity. This set of compounds was analyzed with respect to sigma(1) affinity, sigma(1)/sigma(2) selectivity, lipophilicity (logD(7.4)), lipophilicity-corrected ligand efficiency (LELP), and molecular target interactions. The most promising candidates were pyridyl-substituted thiazole derivatives 33c (2-(1-benzyl-4-ethoxypi-peridin-4-yl)-5-(pyridin-3-yl) thiazole) and 34c (2-(1-benzyl-4-ethoxypiperidin-4-yl)-5-(pyridin-4-yl) thiazole), possessing lownanomolar sigma(1) affinity (K-i = 1.3 and 1.9 nm), high sigma(1)/sigma(2) selectivity (&gt;1500-fold), low lipophilicity (logD(7.4) = 1.8) and very good ligand efficiency (LELP = 5.5), indicating promising pharmacodynamics and pharmacokinetics. Molecular simulation studies, including docking and deconvolution of the free binding energy into its major components, led to decreased hydrophobic stabilization of pyridyl derivatives 33c and 34c, which was compensated by lower desolvation energy.

    DOI PubMed

  • Synthesis of multiply arylated pyridines

    Takashi Asako, Wakana Hayashi, Kazuma Amaike, Shin Suzuki, Kenichiro Itami, Kei Muto, Junichiro Yamaguchi

    TETRAHEDRON   73 ( 26 ) 3669 - 3676  2017.06

     View Summary

    We have achieved a synthesis of multiply arylated pyridines by using a [4 + 2] cycloaddition of 2,4-diaryl-5-chloroxazoles and cinnamic acids as a key reaction. The resulting hydroxytriarylpyridines can be derivatized into triarylpyridines, tetraarylpyridines and pentaarylpyridines by sequential cross couplings. This synthetic method allows for facile and rapid access to highly arylated pyridines with different aryl substituents. (C) 2017 Elsevier Ltd. All rights reserved.

    DOI

  • Rh-catalyzed regiodivergent hydrosilylation of acyl aminocyclopropanes controlled by monophosphine ligands

    Hiroki Kondo, Kenichiro Itami, Junichiro Yamaguchi

    CHEMICAL SCIENCE   8 ( 5 ) 3799 - 3803  2017.05

     View Summary

    A Rh-catalyzed regiodivergent hydrosilylation of acyl aminocyclopropanes has been developed. Acyl aminocyclopropanes were reacted with hydrosilanes in the presence of Rh catalysts to afford ring-opened hydrosilylated adducts through carbon-carbon (C-C) bond cleavage of the cyclopropane ring. The regioselectivity of the addition of silanes (linear or branched) can be switched by changing the monophosphine ligand. This C-C bond cleavage/hydrosilylation methodology is applicable to the synthesis of silanediol precursors.

    DOI

  • Theoretical Elucidation of Potential Enantioselectivity in a Pd-Catalyzed Aromatic C-H Coupling Reaction

    Yoshio Nishimoto, Hiroki Kondo, Kazur Yamaguchi, Daisuke Yokogawa, Junichiro Yamaguchi, Kenichiro Itami, Stephan Irle

    JOURNAL OF ORGANIC CHEMISTRY   82 ( 9 ) 4900 - 4906  2017.05

     View Summary

    The mechanism of an aromatic C-H coupling reaction between heteroarenes and arylboronic acids using a Pd catalyst was theoretically and experimentally investigated. We identified the C-B transmetalation as the rate determining step. The (S)-catalyst-reactant complex was found to be stabilized by hyperconjugation between pi-orbitals on the tolyl group and the S-O sigma* antibonding orbital in the catalyst ligand. Our findings suggest routes for the design of new, improved Pd catalysts with higher stereoselectivity.

    DOI

  • Toward an Ideal Synthesis of (Bio) molecules through Direct Arene Assembling Reactions

    Junichiro Yamaguchi, Kenichiro Itami

    BULLETIN OF THE CHEMICAL SOCIETY OF JAPAN   90 ( 4 ) 367 - 383  2017.04

    Book review, literature introduction, etc.  

     View Summary

    C-H (hetero) arylation of aromatic compounds using transition-metal catalysts has garnered much attention from the synthetic chemistry community as a next-generation coupling method for constructing (hetero) biaryl motifs. This account describes our recent achievements in transitionmetal-catalyzed aromatic C-H arylation and its applications to the synthesis of bioactive molecules.

    DOI

  • Decarbonylative Diaryl Ether Synthesis by Pd and Ni Catalysis

    Ryosuke Takise, Ryota Isshiki, Kei Muto, Kenichiro Itami, Junichiro Yamaguchi

    JOURNAL OF THE AMERICAN CHEMICAL SOCIETY   139 ( 9 ) 3340 - 3343  2017.03

     View Summary

    Because diaryl ethers are present as an important motif in pharmaceuticals and natural products, extensive studies for the development of novel methods have been conducted. A conventional method for the construction of the diaryl ether moiety is the intermolecular cross-coupling reaction of aryl halides and phenols with a copper or palladium catalyst. We developed a catalytic decarbonylative etherification of aromatic esters using a palladium or nickel catalyst with our enabling diphosphine ligand to give the corresponding diaryl ethers. The present reaction can be conducted on grain scale in excellent yield. This reaction not only functions in an intramolecular setting but also allows for a crossetherification using other phenols.

    DOI

  • Syntheses of Biologically Active 2-Arylcyclopropylamines

    Shin Miyamura, Kenichiro Itami, Junichiro Yamaguchi

    SYNTHESIS-STUTTGART   49 ( 6 ) 1131 - 1149  2017.03

     View Summary

    The 2-arylcyclopropylamine (ACPA) motif is often seen in biologically active compounds. This review focuses on the synthesis of biologically active ACPAs and categorizes, by reaction type, the synthetic methods used toward such compounds.
    1 Introduction
    2 Cyclopropanation Using Diazo Compounds
    2.1 Styrene
    2.2 Cinnamate
    2.3 Vinyl Phthalimide
    2.4 Vinyl Acetamide
    2.5 Oxazolone
    2.6 Diketopiperazine
    3 Cyclopropanation Using Ylides
    3.1 Cinnamate
    3.2 Nitrostyrene
    3.3 Oxirane
    3.4 Nitroacetate
    4 Transformation of Cyclopropanes
    4.1 Iodocyclopropane
    4.2 Aminocyclopropane
    5 Miscellaneous Methods
    5.1 Kulinkovich Reaction
    5.2 Three-Component Reaction
    5.3 Intramolecular Nucleophilic Cyclization
    5.4 Intramolecular Mitsunobu Reaction
    5.5 Rearrangement from Cyclobutanone
    6 Summary

    DOI

  • Palladium-catalyzed Decarbonylative Alkynylation of Aromatic Esters

    Toshimasa Okita, Kazushi Kumazawa, Ryosuke Takise, Kei Muto, Kenichiro Itami, Junichiro Yamaguchi

    CHEMISTRY LETTERS   46 ( 2 ) 218 - 220  2017.02

     View Summary

    A palladium-catalyzed decarbonylative alkynylation reaction of aromatic esters with terminal alkynes is reported. This reaction allows for halogen-free Sonogashira coupling, resulting in various aryl- and heteroarylalkynes. The utility of the reaction was demonstrated by orthogonal coupling reaction.

    DOI

  • Synthesis of fully arylated (hetero)arenes

    Shin Suzuki, Junichiro Yamaguchi

    CHEMICAL COMMUNICATIONS   53 ( 10 ) 1568 - 1582  2017.02

    Book review, literature introduction, etc.  

     View Summary

    © The Royal Society of Chemistry. Multiply arylated arenes are privileged structures with highly useful functions and fascinating optoelectronic and biological properties. This feature article reports the synthesis of fully arylated (hetero)arenes bearing more than two different aryl substituents and categorizes this emerging topic by the type of (hetero)arene core and the type of chemistry employed to install the (hetero)aryl substituents.

    DOI

  • Palladium-Catalyzed Decarbonylative Cross-Coupling of Azinecarboxylates with Arylboronic Acids

    Kei Muto, Taito Hatakeyama, Kenichiro Itami, Junichiro Yamaguchi

    ORGANIC LETTERS   18 ( 19 ) 5106 - 5109  2016.10

     View Summary

    The first palladium-catalyzed decarbonylative coupling of phenyl 2-azinecarboxylates and arylboronic acids is presented. The key for the development of this decarbonylative coupling is the use of Pd/dcype as a catalyst. A wide range of 2-azinecarboxylates can undergo the present coupling reaction to afford 2-arylazines. By combination with previously reported nickel-catalyzed decarbonylative coupling, we achieved a chemoselective sequential decarbonylative coupling of pyridine dicarboxylate to synthesize 2,4-diarylpyridine.

    DOI

  • Cyanation of Phenol Derivatives with Aminoacetonitriles by Nickel Catalysis

    Ryosuke Takise, Kenichiro Itami, Junichiro Yamaguchi

    ORGANIC LETTERS   18 ( 17 ) 4428 - 4431  2016.09

     View Summary

    Generation of useful arylnitrile structures from simple aromatic feedstock chemicals represents a fundamentally important reaction in chemical synthesis. The first nickel-catalyzed cyanation of phenol derivatives with metal-free cyanating agents, aminoacetonitriles, is described. A nickel-based catalytic system consisting of a unique diphosphine ligand such as dcype or dcypt enables the cyanation of versatile phenol derivatives such as aryl carbamates and aryl pivalates. The use of aminoacetonitriles as a cyanating agent leads to an environmentally and easy-to-use method for arylnitrile synthesis.

    DOI

  • Nickel-Catalyzed Aromatic C–H Functionalization

    Junichiro Yamaguchi, Kei Muto, Kenichiro Itami

    Topics in Current Chemistry   374 ( 4 )  2016.08

    Book review, literature introduction, etc.  

     View Summary

    Catalytic C–H functionalization using transition metals has received significant interest from organic chemists because it provides a new strategy to construct carbon–carbon bonds and carbon–heteroatom bonds in highly functionalized, complex molecules without pre-functionalization. Recently, inexpensive catalysts based on transition metals such as copper, iron, cobalt, and nickel have seen more use in the laboratory. This review describes recent progress in nickel-catalyzed aromatic C–H functionalization reactions classified by reaction types and reaction partners. Furthermore, some reaction mechanisms are described and cutting-edge syntheses of natural products and pharmaceuticals using nickel-catalyzed aromatic C–H functionalization are presented.

    DOI

  • Nickel-Catalyzed Aromatic C-H Functionalization

    Junichiro Yamaguchi, Kei Muto, Kenichiro Itami

    TOPICS IN CURRENT CHEMISTRY   374 ( 4 )  2016.08

    Book review, literature introduction, etc.  

     View Summary

    Catalytic C-H functionalization using transition metals has received significant interest from organic chemists because it provides a new strategy to construct carbon-carbon bonds and carbon-heteroatom bonds in highly functionalized, complex molecules without pre-functionalization. Recently, inexpensive catalysts based on transition metals such as copper, iron, cobalt, and nickel have seen more use in the laboratory. This review describes recent progress in nickelcatalyzed aromatic C-H functionalization reactions classified by reaction types and reaction partners. Furthermore, some reaction mechanisms are described and cutting-edge syntheses of natural products and pharmaceuticals using nickel-catalyzed aromatic C-H functionalization are presented.

    DOI

  • The AMOR Arabinogalactan Sugar Chain Induces Pollen-Tube Competency to Respond to Ovular Guidance.

    Akane G Mizukami, Rie Inatsugi, Jiao Jiao, Toshihisa Kotake, Keiko Kuwata, Kento Ootani, Satohiro Okuda, Subramanian Sankaranarayanan, Yoshikatsu Sato, Daisuke Maruyama, Hiroaki Iwai, Estelle Garénaux, Chihiro Sato, Ken Kitajima, Yoichi Tsumuraya, Hitoshi Mori, Junichiro Yamaguchi, Kenichiro Itami, Narie Sasaki, Tetsuya Higashiyama

    Current biology : CB   26 ( 8 ) 1091 - 7  2016.04  [International journal]

     View Summary

    Precise directional control of pollen-tube growth by pistil tissue is critical for successful fertilization of flowering plants [1-3]. Ovular attractant peptides, which are secreted from two synergid cells on the side of the egg cell, have been identified [4-6]. Emerging evidence suggests that the ovular directional cue is not sufficient for successful guidance but that competency control by the pistil is critical for the response of pollen tubes to the attraction signal [1, 3, 7]. However, the female molecule for this competency induction has not been reported. Here we report that ovular methyl-glucuronosyl arabinogalactan (AMOR) induces competency of the pollen tube to respond to ovular attractant LURE peptides in Torenia fournieri. We developed a method for assaying the response capability of a pollen tube by micromanipulating an ovule. Using this method, we showed that pollen tubes growing through a cut style acquired a response capability in the medium by receiving a sufficient amount of a factor derived from mature ovules of Torenia. This factor, named AMOR, was identified as an arabinogalactan polysaccharide, the terminal 4-O-methyl-glucuronosyl residue of which was necessary for its activity. Moreover, a chemically synthesized disaccharide, the β isomer of methyl-glucuronosyl galactose (4-Me-GlcA-β-(1→6)-Gal), showed AMOR activity. No specific sugar-chain structure of plant extracellular matrix has been identified as a bioactive molecule involved in intercellular communication. We suggest that the AMOR sugar chain in the ovary renders the pollen tube competent to the chemotropic response prior to final guidance by LURE peptides.

    DOI PubMed

  • Synthesis of Triarylpyridines in Thiopeptide Antibiotics by Using a C-H Arylation/Ring-Transformation Strategy

    Kazuma Amaike, Kenichiro Itami, Junichiro Yamaguchi

    CHEMISTRY-A EUROPEAN JOURNAL   22 ( 13 ) 4384 - 4388  2016.03

     View Summary

    We have described a C-H arylation/ring-transformation strategy for the synthesis of triarylpyridines, which form the core structure of thiopeptide antibiotics. This synthetic method readily gave 2,3,6-triarylpyridines in a regioselective manner by a two-phase approach: C-H arylation (a nickel-catalyzed decarbonylative Suzuki-Miyaura cross-coupling and decarbonylative C-H coupling for the synthesis of 2,4-diaryloxazoles) and ring transformation ([4+2] cycloaddition of 2,4-diaryloxazoles with (hetero)arylacrylic acids). To showcase these methods, we have accomplished the formal synthesis of thiopeptide antibiotics GE2270s and amythiamicins.

    DOI PubMed

  • Synthesis of Natural Products and Pharmaceuticals via Catalytic C-H Functionalization

    Junichiro Yamaguchi, Kazuma Amaike, Kenichiro Itami

    Transition Metal-Catalyzed Heterocycle Synthesis via C-H Activation     505 - 550  2016.01

     View Summary

    The synthesis of natural products and pharmaceuticals, particularly those containing heterocyclic frameworks, can be dramatically simplified by using catalytic C-H functionalization. C-H functionalization has gathered significant interest from the organic synthesis community because it provides a new strategy to construct carbon-carbon and carbon-heteroatom bonds in highly functionalized, complex molecules without prefunctionalization. In this book chapter, methods in heterocycle substitution and synthesis using catalytic C-H functionalization are classified by heterocycle, with specific focus on the cutting-edge synthesis of natural products and pharmaceuticals.

    DOI

  • C-H activation enables a rapid structure-activity relationship study of arylcyclopropyl amines for potent and selective LSD1 inhibitors

    Shin Miyamura, Misaho Araki, Yosuke Ota, Yukihiro Itoh, Shusuke Yasuda, Mitsuharu Masuda, Tomoyuki Taniguchi, Yoshihiro Sowa, Toshiyuki Sakai, Takayoshi Suzuki, Kenichiro Itami, Junichiro Yamaguchi

    Organic and Biomolecular Chemistry   14 ( 36 ) 8576 - 8585  2016

     View Summary

    © 2016 The Royal Society of Chemistry. We describe the structure-activity relationship of various arylcyclopropylamines (ACPAs), which are potent LSD1 inhibitors. More than 45 ACPAs were synthesized rapidly by an unconventional method that we have recently developed, consisting of a C-H borylation and cross-coupling sequence starting from cyclopropylamine. We also generated NCD38 derivatives, which are known as LSD1 selective inhibitors, and discovered a more effective inhibitor compared to the original NCD38.

    DOI PubMed

  • Microwave-assisted regioselective direct C-H arylation of thiazole derivatives leading to increased sigma(1) receptor affinity

    Artur Kokornaczyk, Dirk Schepmann, Junichiro Yamaguchi, Kenichiro Itami, Bernhard Wuensch

    MEDCHEMCOMM   7 ( 2 ) 327 - 331  2016

     View Summary

    New thiazole analogues 2 of spirocyclic thiophenes 1, which are known to show high sigma(1) receptor affinities, have been developed as potentially better sigma(1) receptor ligands. To introduce an aryl group onto the thiazole core of 2 (C4 or C5 positions), we used Pd-catalyzed regioselective C-H arylation reactions. The Pd-catalyzed C5 arylation of 2a could be considerably improved by using microwave irradiation technique. The Pd-catalyzed C4 arylation of thiazole 2a with arylboronic acid 6 could be achieved in the presence of Pd(OAc) 2, 1,10-phenanthroline, TEMPO, and LiBF4. Under these conditions, the tertiary amine and the tertiary alcohol were well-tolerated. The regioselective arylation of 2a led to new compounds 2b and 2c, with a 4-tolyl moiety in the C5-and C4-positions, displaying five to nine-fold increased sigma(1) affinity. The same sigma(1) affinity of the regioisomeric thiazoles 2b and 2c can be explained by fast rotation around the piperidinethiazole bond. Compared to spirocyclic thiophenes 1, thiazoles 2 are considerably more polar.

    DOI

  • C-H Activation Generates Period-Shortening Molecules That Target Cryptochrome in the Mammalian Circadian Clock

    Tsuyoshi Oshima, Iori Yamanaka, Anupriya Kumar, Junichiro Yamaguchi, Taeko Nishiwaki-Ohkawa, Kei Muto, Rika Kawamura, Tsuyoshi Hirota, Kazuhiro Yagita, Stephan Irle, Steve A. Kay, Takashi Yoshimura, Kenichiro Itami

    ANGEWANDTE CHEMIE-INTERNATIONAL EDITION   54 ( 24 ) 7193 - 7197  2015.06

     View Summary

    The synthesis and functional analysis of KL001 derivatives, which are modulators of the mammalian circadian clock, are described. By using cutting-edge C-H activation chemistry, a focused library of KL001 derivatives was rapidly constructed, which enabled the identification of the critical sites on KL001 derivatives that induce a rhythm-changing activity along with the components that trigger opposite modes of action. The first period-shortening molecules that target the cryptochrome (CRY) were thus discovered. Detailed studies on the effects of these compounds on CRY stability implicate the existence of an as yet undiscovered regulatory mechanism.

    DOI PubMed

  • Decarbonylative organoboron cross-coupling of esters by nickel catalysis

    Kei Muto, Junichiro Yamaguchi, Djamaladdin G. Musaev, Kenichiro Itami

    NATURE COMMUNICATIONS   6  2015.06

     View Summary

    The Suzuki-Miyaura cross-coupling is a metal-catalysed reaction in which boron-based nucleophiles and halide-based electrophiles are reacted to form a single molecule. This is one of the most reliable tools in synthetic chemistry, and is extensively used in the synthesis of pharmaceuticals, agrochemicals and organic materials. Herein, we report a significant advance in the choice of electrophilic coupling partner in this reaction. With a user-friendly and inexpensive nickel catalyst, a range of phenyl esters of aromatic, heteroaromatic and aliphatic carboxylic acids react with boronic acids in a decarbonylative manner. Overall, phenyl ester moieties function as leaving groups. Theoretical calculations uncovered key mechanistic features of this unusual decarbonylative coupling. Since extraordinary numbers of ester-containing molecules are available both commercially and synthetically, this new 'ester' cross-coupling should find significant use in synthetic chemistry as an alternative to the standard halide-based Suzuki-Miyaura coupling.

    DOI

  • Synthesis and characterization of hexaarylbenzenes with five or six different substituents enabled by programmed synthesis

    Shin Suzuki, Yasutomo Segawa, Kenichiro Itami, Junichiro Yamaguchi

    NATURE CHEMISTRY   7 ( 3 ) 227 - 233  2015.03

     View Summary

    Since its discovery in 1825, benzene has served as one of the most used and indispensable building blocks of chemical compounds, ranging from pharmaceuticals and agrochemicals to plastics and those used in organic electronic devices. Benzene has six hydrogen atoms that can each be replaced by different substituents, which means that the structural diversity of benzene derivatives is intrinsically extraordinary. The number of possible substituted benzenes from n different substituents is (2n + 2n(2) + 4n(3) + 3n(4) + n(6))/12. However, owing to a lack of general synthetic methods for making multisubstituted benzenes, this potentially huge structural diversity has not been fully exploited. Here, we describe a programmed synthesis of hexaarylbenzenes using C-H activation, cross-coupling and [4+2] cycloaddition reactions. The present method allows for the isolation and structure-property characterization of hexaarylbenzenes with distinctive aryl substituents at all positions for the first time. Moreover, the established protocol can be applied to the synthesis of tetraarylnaphthalenes and pentaarylpyridines.

    DOI

  • Synthesis, binding affinity and structure-activity relationships of novel, selective and dual targeting CCR2 and CCR5 receptor antagonists

    Anna Junker, Artur K. Kokornaczyk, Annelien J. M. Zweemer, Bastian Frehland, Dirk Schepmann, Junichiro Yamaguchi, Kenichiro Itami, Andreas Faust, Sven Hermann, Stefan Wagner, Michael Schaefers, Michael Koch, Christina Weiss, Laura H. Heitman, Klaus Kopka, Bernhard Wuensch

    ORGANIC & BIOMOLECULAR CHEMISTRY   13 ( 8 ) 2407 - 2422  2015

     View Summary

    CCR2 and CCR5 receptors play a key role in the development and progression of several inflammatory, cardiovascular and autoimmune diseases. Therefore, dual targeting of both receptors appeals as a promising strategy for the treatment of such complex, multifactorial disorders. Herein we report on the design, synthesis and biological evaluation of benzo[7] annulene- and [7] annulenothiophene-based selective and dual CCR2 and CCR5 receptor antagonists. Intermediates were designed in such a way that diversification could be introduced at the end of the synthesis. Starting from the lead compound TAK-779 (1), the quaternary ammonium moiety was exchanged by different non-charged moieties, the 4-methylphenyl moiety was extensively modified and the benzo[7]annulene core was replaced bioisosterically by the [7]annulenothiophene system. The naphthyl derivative 9h represents the most promising dual antagonist (K-i (CCR2) = 25 nM, IC50 (CCR5) = 17 nM), whereas the 6-isopropoxy-3-pyridyl and 4-methoxycarbonylphenyl derivatives 9k and 9r show more than 20-fold selectivity for the CCR2 (K-i = 19 nM) over the CCR5 receptor.

    DOI PubMed

  • C-H arylation and alkenylation of imidazoles by nickel catalysis: solvent-accelerated imidazole C-H activation

    Kei Muto, Taito Hatakeyama, Junichiro Yamaguchi, Kenichiro Itami

    CHEMICAL SCIENCE   6 ( 12 ) 6792 - 6798  2015

     View Summary

    The first nickel-catalyzed C-H arylations and alkenylations of imidazoles with phenol and enol derivatives are described. Under the influence of Ni(OTf)(2)/dcype/K3PO4 (dcype: 1,2-bis(dicyclohexylphosphino) ethane) in t-amyl alcohol, imidazoles can undergo C-H arylation with phenol derivatives. The C-H arylation of imidazoles with chloroarenes as well as that of thiazoles and oxazoles with phenol derivatives can also be achieved with this catalytic system. By changing the ligand to dcypt (3,4-bis(dicyclohexylphosphino) thiophene), enol derivatives could also be employed as coupling partners achieving the C-H alkenylation of imidazoles as well as thiazoles and oxazoles. Thus, a range of C2-arylated and alkenylated azoles can be synthesized using this newly developed nickel-based catalytic system. The key to the success of the C-H coupling of imidazoles is the use of a tertiary alcohol as solvent. This also allows the use of an air-stable nickel(II) salt as the catalyst precursor.

    DOI

  • Stereodivergent Synthesis of Arylcyclopropylamines by Sequential C-H Borylation and Suzuki-Miyaura Coupling

    Shin Miyamura, Misaho Araki, Takayoshi Suzuki, Junichiro Yamaguchi, Kenichiro Itami

    ANGEWANDTE CHEMIE-INTERNATIONAL EDITION   54 ( 3 ) 846 - 851  2015.01

     View Summary

    A step-economical and stereodivergent synthesis of privileged 2-arylcyclopropylamines (ACPAs) through a C-(sp(3))-H borylation and Suzuki-Miyaura coupling sequence has been developed. The iridium-catalyzed C-H borylation of N-cyclopropylpivalamide proceeds with cis selectivity. The subsequent B-cyclopropyl Suzuki-Miyaura coupling catalyzed by [PdCl2(dppf)]/Ag2O proceeds with retention of configuration at the carbon center bearing the Bpin group, while epimerization at the nitrogen-bound carbon atoms of both the starting materials and products is observed under the reaction conditions. This epimerization is, however, suppressed in the presence of O-2. The present new ACPA synthesis results in not only a significant reduction in the steps required for making ACPA derivatives, but also the ability to access either isomer (cis or trans) by simply changing the atmosphere (N-2 or O-2) in the coupling stage.

    DOI PubMed

  • Ni-Catalyzed alpha-arylation of esters and amides with phenol derivatives

    Eva Koch, Ryosuke Takise, Armido Studer, Junichiro Yamaguchi, Kenichiro Itami

    CHEMICAL COMMUNICATIONS   51 ( 5 ) 855 - 857  2015

     View Summary

    A nickel-catalyzed alpha-arylation of esters and amides with phenol derivatives has been accomplished. In the presence of our unique nickel catalyst, prepared in situ from Ni(cod)(2), 3,4-bis(dicyclohexyl-phosphino) thiophene (dcypt), and K3PO4, various esters and amides undergo alpha-arylation with O-arylpivalates or O-arylcarbamates to afford the corresponding coupling products. The thus obtained alpha-aryl esters and amides are useful precursors of privileged motifs such as alpha-arylcarboxylic acids and beta-arylamines.

    DOI PubMed

  • Concise Syntheses of Dictyodendrins A and F by a Sequential C-H Functionalization Strategy

    Atsushi D. Yamaguchi, Kathryn M. Chepiga, Junichiro Yamaguchi, Kenichiro Itami, Huw M. L. Davies

    JOURNAL OF THE AMERICAN CHEMICAL SOCIETY   137 ( 2 ) 644 - 647  2015.01

     View Summary

    Syntheses of dictyodendrins A and F have been achieved using a sequential C-H functionalization strategy. The N-alkylpyrrole core is fully functionalized by means of a rhodium(I)-catalyzed C-H arylation at the C3-position, a rhodium(II)-catalyzed double C-H insertion at the C2- and C5-positions, and a Suzuki-Miyaura cross-coupling reaction at the C4-position. The syntheses of dictyodendrins A and F were completed by formal 6p-electrocyclization to generate the pyrrolo[2,3-c]carbazole core of the natural products.

    DOI PubMed

  • Key Mechanistic Features of Ni-Catalyzed C-H/C-O Biaryl Coupling of Azoles and Naphthalen-2-yl Pivalates

    Huiying Xu, Kei Muto, Junichiro Yamaguchi, Cunyuan Zhao, Kenichiro Itami, Djamaladdin G. Musaev

    JOURNAL OF THE AMERICAN CHEMICAL SOCIETY   136 ( 42 ) 14834 - 14844  2014.10

     View Summary

    The mechanism of the Ni-dcype-catalyzed C-H/C-O coupling of benzoxazole and naphthalen-2-yl pivalate was studied. Special attention was devoted to the base effect in the C-O oxidative addition and C-H activation steps as well as the C-H substrate effect in the C-H activation step. No base effect in the C(aryl)-O oxidative addition to Ni-dcype was found, but the nature of the base and C-H substrate plays a crucial role in the following C-H activation. In the absence of base, the azole C-H activation initiated by the C-O oxidative addition product Ni(dcype)(Naph)(PivO), 1B, proceeds via Delta G = 34.7 kcal/mol barrier. Addition of Cs2CO3 base to the reaction mixture forms the Ni(dcype)(Naph)[PivOCs.CsCO3], 3_Cs_clus, cluster complex rather than undergoing PivO(-) -&gt; CsCO3(-) ligand exchange. Coordination of azole to the resulting 3_Cs_clus complex forms intermediate with a weak Cs-heteroatom(azole) bond, the existence of which increases acidity of the activated C-H bond and reduces C-H activation barrier. This conclusion from computation is consistent with experiments showing that the addition of Cs2CO3 to the reaction mixture of 1B and benzoxazole increases yield of C-H/C-O coupling from 32% to 67% and makes the reaction faster by 3-fold. This emerging mechanistic knowledge was validated by further exploring base and C-H substrate effects via replacing Cs2CO3 with K2CO3 and benzoxazole (1a) with 1H-benzo[d]imidazole (1b) or quinazoline (1c). We proposed the modified catalytic cycle for the Ni(cod)(dcype)-catalyzed C-H/C-O coupling of benzoxazole and naphthalen-2-yl pivalate.

    DOI PubMed

  • beta-Selective C-H Arylation of Pyrroles Leading to Concise Syntheses of Lamellarins C and I

    Kirika Ueda, Kazuma Amaike, Richard M. Maceiczyk, Kenichiro Itami, Junichiro Yamaguchi

    JOURNAL OF THE AMERICAN CHEMICAL SOCIETY   136 ( 38 ) 13226 - 13232  2014.09

     View Summary

    The first general beta-selective C-H arylation of pyrroles has been developed by using a rhodium catalyst. This C H arylation reaction, which is retrosynthetically straightforward but results in unusual regioselectivity, could result in de novo syntheses of pyrrole-derived natural products and pharmaceuticals. As such, we have successfully synthesized polycyclic marine pyrrole alkaloids, lamellarins C and I, by using this beta-selective arylation of pyrroles with aryl iodides (C-H/C-I coupling) and a new double C-H/C-H coupling as key steps.

    DOI PubMed

  • Branch-Selective Allylic C-H Carboxylation of Terminal Alkenes by Pd/sox Catalyst

    Hiroki Kondo, Feng Yu, Junichiro Yamaguchi, Guosheng Liu, Kenichiro Itami

    ORGANIC LETTERS   16 ( 16 ) 4212 - 4215  2014.08

     View Summary

    A ligand-controlled branch-selective allylic C-H carboxylation through Pd catalysis is described. The developed catalytic system, which consists of Pd(OAc)(2), sulfoxide oxazoline (sox) as a ligand and benzoquinone as an oxidant, couples terminal alkenes and carboxylic acids to furnish the corresponding branched allylic esters with high regioselectivity.

    DOI PubMed

  • Synthesis of dictyodendrin A via sequential C-H functionalizations

    Kathryn M. Chepiga, Atsushi D. Yamaguchi, Junichiro Yamaguchi, Kenichiro Itami, Huw M. L. Davies

    ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY   248  2014.08

    Research paper, summary (international conference)  

  • 2,4-and 2,5-Disubstituted Arylthiazoles: Rapid Synthesis by C-H Coupling and Biological Evaluation

    Lilia Lohrey, Takahiro N. Uehara, Satoshi Tani, Junichiro Yamaguchi, Hans-Ulrich Humpf, Kenichiro Itami

    EUROPEAN JOURNAL OF ORGANIC CHEMISTRY   2014 ( 16 ) 3387 - 3394  2014.06

     View Summary

    Life-threatening infections caused by bacteria that have developed resistance to common antibiotics, such as methicillin-resistant Staphylococcus aureus (MRSA), have become a serious problem in hospitals and other areas all over the world. Thus, the development of an effective class of antibiotics against these bacteria is an urgent subject. Herein, we report a step-economical and diversity-oriented synthesis of a series of 2-arylidenehydrazinyl-4-arylthiazole and 2-arylidenehydrazinyl-5-arylthiazole analogues that utilizes C-H coupling methodologies. A library of 54 new congeners were synthesized and tested for their biological potential. Moreover, new knowledge regarding the structure-activity relationships (SARs) of these heterobiaryl compounds was collected.

    DOI

  • Nickel-Catalyzed alpha-Arylation of Ketones with Phenol Derivatives

    Ryosuke Takise, Kei Muto, Junichiro Yamaguchi, Kenichiro Itami

    ANGEWANDTE CHEMIE-INTERNATIONAL EDITION   53 ( 26 ) 6791 - 6794  2014.06

     View Summary

    The nickel-catalyzed alpha-arylation of ketones with readily available phenol derivatives (esters and carbamates) provides access to useful alpha-arylketones. For this transformation, 3,4-bis(dicyclohexylphosphino)thiophene (dcypt) was identified as a new, enabling, air-stable ligand for this transformation. The intermediate of an assumed C-O oxidative addition was isolated and characterized by X-ray crystal-structure analysis.

    DOI PubMed

  • Late-stage C-H coupling enables rapid identification of HDAC inhibitors: Synthesis and evaluation of NCH-31 analogues

    Hiromi Sekizawa, Kazuma Amaike, Yukihiro Itoh, Takayoshi Suzuki, Kenichiro Itami, Junichiro Yamaguchi

    ACS Medicinal Chemistry Letters   5 ( 5 ) 582 - 586  2014.05

     View Summary

    We previously reported the discovery of NCH-31, a potent histone deacetylase (HDAC) inhibitor. By utilizing our C-H coupling reaction, we rapidly synthesized 16 analogues (IYS-1 through IYS-15 and IYS-Me) of NCH-31 with different aryl groups at the C4-position of 2-aminothiazole core of NCH-31. Subsequent biological testing of these derivatives revealed that 3-fluorophenyl (IYS-10) and 4-fluorophenyl (IYS-15) derivatives act as potent pan-HDAC inhibitor. Additionally, 4-methylphenyl (IYS-1) and 3-fluoro-4-methylphenyl (IYS-14) derivatives acted as HDAC6-insensitive inhibitors. The present work clearly shows the power of the late-stage C-H coupling approach to rapidly identify novel and highly active/selective biofunctional molecules. © 2014 American Chemical Society.

    DOI

  • Programmed synthesis of arylthiazoles through sequential C-H couplings

    Satoshi Tani, Takahiro N. Uehara, Junichiro Yamaguchi, Kenichiro Itami

    CHEMICAL SCIENCE   5 ( 1 ) 123 - 135  2014

     View Summary

    A programmed synthesis of privileged arylthiazoles via sequential C-H couplings catalyzed by palladium or nickel catalysts has been accomplished. This versatile protocol can supply all possible arylthiazole substitution patterns (2-aryl, 4-aryl, 5-aryl, 2,4-diaryl, 2,5-diaryl, 4,5-diaryl, and 2,4,5-triaryl) from an unfunctionalized thiazole platform by 11 distinct synthetic routes. We have generated over 150 arylthiazoles by using this methodology. We have applied this method to the rapid synthesis of fatostatin (SREBP inhibitor), and the gram-scale synthesis of triarylthiazoles has been demonstrated.

    DOI

  • Diverse modifications of the 4-methylphenyl moiety of TAK-779 by late-stage Suzuki-Miyaura cross-coupling

    Anna Junker, Dirk Schepmann, Junichiro Yamaguchi, Kenichiro Itami, Andreas Faust, Klaus Kopka, Stefan Wagner, Bernhard Wuensch

    ORGANIC & BIOMOLECULAR CHEMISTRY   12 ( 1 ) 177 - 186  2014.01

     View Summary

    Chemokine receptor 5 (CCR5) antagonists provide a new therapeutic approach in the treatment of HIV-1 (AIDS). TAK-779 displays high affinity and selectivity for the CCR5 receptor and serves as a lead compound for the development of further antagonists. In order to increase the oral bioavailability replacement of the quaternary ammonium structure by a tertiary amine and modification of the 4-methylphenyl moiety were envisaged. Herein, a new synthetic strategy for the development of TAK-779 analogs by late stage diversification is reported. The Suzuki-Miyaura cross-coupling reactions allowed various modifications of the central amide building block 3 at the end of the synthesis leading to compounds 2f and 2h with a promising CCR5 binding affinity.

    DOI PubMed

  • Manganese-catalyzed intermolecular C-H/C-H coupling of carbonyls and heteroarenes

    Keika Hattori, Asraa Ziadi, Kenichiro Itami, Junichiro Yamaguchi

    CHEMICAL COMMUNICATIONS   50 ( 31 ) 4105 - 4107  2014

     View Summary

    Manganese-catalyzed intermolecular C-H/C-H coupling of carbonyls and heteroarenes has been developed. The presence of NaIO4 as an oxidant is crucial for the catalytic reaction. These new, inexpensive reaction conditions allow the gram-scale synthesis of a-heteroaryl carboxylic acids.

    DOI PubMed

  • Biaryl Synthesis through Metal-Catalyzed C-H Arylation

    Junichiro Yamaguchi, Kenichiro Itami

    Metal Catalyzed Cross-Coupling Reactions and More   3   1315 - 1387  2013.11

    DOI

  • Isolation, structure, and reactivity of an arylnickel(II) pivalate complex in catalytic C-H/C-O biaryl coupling

    Kei Muto, Junichiro Yamaguchi, Aiwen Lei, Kenichiro Itami

    Journal of the American Chemical Society   135 ( 44 ) 16384 - 16387  2013.11

     View Summary

    We describe mechanistic studies of a C-H/C-O biaryl coupling of 1,3-azoles and aryl pivalates catalyzed by Ni(cod)2/dcype. This study not only supports a catalytic cycle consisting of C-O oxidative addition, C-H nickelation, and reductive elimination but also provides insight into the dramatic ligand effect in C-H/C-O coupling. We have achieved the first synthesis, isolation and structure elucidation of an arylnickel(II) pivalate, which is an intermediate in the catalytic cycle after oxidative addition of a C-O bond. Furthermore, kinetic studies and kinetic isotope effect investigations reveal that the C-H nickelation is the turnover-limiting step in the catalytic cycle. © 2013 American Chemical Society.

    DOI PubMed

  • Palladium-Catalyzed C-H and C-N Arylation of Aminothiazoles with Arylboronic Acids

    Takahiro N. Uehara, Junichiro Yamaguchi, Kenichiro Itami

    ASIAN JOURNAL OF ORGANIC CHEMISTRY   2 ( 11 ) 938 - 942  2013.11

    DOI

  • C-H Alkenylation of Azoles with Enols and Esters by Nickel Catalysis

    Lingkui Meng, Yuko Kamada, Kei Muto, Junichiro Yamaguchi, Kenichiro Itami

    ANGEWANDTE CHEMIE-INTERNATIONAL EDITION   52 ( 38 ) 10048 - 10051  2013.09

     View Summary

    Rather u(Ni)que: Two new C-H alkenylation reactions, that is C-H/CO alkenylation and decarbonylative C-H alkenylation, of azoles are uniquely catalyzed by Ni/dcype. These azole alkenylation reactions are successfully applied to the convergent formal synthesis of siphonazoleB. © 2013 WILEY-VCH Verlag GmbH &amp; Co. KGaA, Weinheim.

    DOI PubMed

  • Nickel-Catalyzed Direct Coupling of Heteroarenes

    Junichiro Yamaguchi, Kei Muto, Kazuma Amaike, Takuya Yamamoto, Kenichiro Itami

    JOURNAL OF SYNTHETIC ORGANIC CHEMISTRY JAPAN   71 ( 6 ) 576 - 587  2013.06

     View Summary

    Nickel-catalyzed cross-coupling reactions have recently been receiving significant attention from the synthetic community as a way to construct carbon-carbon or carbon-heteroatom bonds, because nickel catalysts are less expensive and less toxic than palladium catalysts.We herein describe our recent developments in nickel-catalyzed biaryl coupling methodology, along with mechanistic studies and applications to the synthesis of natural products and pharmaceuticals. In particular, we focus on nickel-catalyzed direct coupling reactions in which "unreactive" bonds such as C-H, C-O, and C-C bonds are converted into biaryl moieties.

    DOI

  • 脱エステル型C-Hカップリング : ビアリール化合物の安価・短工程の合成が可能に

    山口 潤一郎, 伊丹 健一郎

    化学 = Chemistry   68 ( 4 ) 35 - 39  2013.04

    CiNii

  • Improvement of sigma(1) receptor affinity by late-stage C-H-bond arylation of spirocyclic lactones

    Christina Meyer, Benedikt Neue, Dirk Schepmann, Shuichi Yanagisawa, Junichiro Yamaguchi, Ernst-Ulrich Wuerthwein, Kenichiro Itami, Bernhard Wuensch

    BIOORGANIC & MEDICINAL CHEMISTRY   21 ( 7 ) 1844 - 1856  2013.04

     View Summary

    The direct C-H-bond arylation of the complex spirocyclic lactones 13, 14, and 18 allows the introduction of diverse aryl moieties in the last step of the synthesis. A selective alpha-arylation of the thiophene moiety was performed with the catalytic system PdCl2/2,2'-bipyridyl/Ag2CO3, whereas the beta-position of the thiophene ring was addressed by using the alternative catalytic system PdCl2/P[OCH(CF3)(2)](3)/Ag2CO3. Due to electronic and steric reasons the arylation of the five-membered lactone 18 occurred in both alpha-positions providing 4'-mono-, 6'-mono- and 4',6'-diarylated thiophenes 22-26a-c. Compounds with an additional aryl moiety at the 'upper left (top)' position (1'-position of 13, 3'-position of 14, 4'-position of 18) showed increased sigma(1) affinity compared to the non-arylated parent compounds. A phenyl moiety at the 'left' position (2'-position in 20a) also increased the sigma(1) affinity but to a lower extent. A considerable reduction of sigma(1) affinity was observed after introducing an aryl moiety in 6'-position of 18, which might result from shielding the tertiary amine, which is crucial for interaction with the sigma(1) receptor. The discussion of the experimental results is supported by high-level quantum chemical DFT-calculations of the NBO-charges of 13 and 18 and the relative energies of the related arylated products. (C) 2013 Elsevier Ltd. All rights reserved.

    DOI PubMed

  • Recent Progress in Nickel-Catalyzed Biaryl Coupling

    Junichiro Yamaguchi, Kei Muto, Kenichiro Itami

    EUROPEAN JOURNAL OF ORGANIC CHEMISTRY   ( 1 ) 19 - 30  2013.01

    Book review, literature introduction, etc.  

     View Summary

    Nickel catalysis for biaryl coupling reactions has received significant attention as a less expensive and less toxic alternative to "standard" palladium catalysis. Here we describe recent developments in nickel-catalyzed biaryl coupling methodology, along with mechanistic studies and applications. In particular we focus on nickel-catalyzed coupling reactions in which "unreactive" bonds such as C-H, C-O, and C-C bonds are converted into biaryl moieties.

    DOI

  • Synthesis of thiophene-based TAK-779 analogues by C-H arylation

    Anna Junker, Junichiro Yamaguchi, Kenichiro Itami, Bernhard Wünsch

    Journal of Organic Chemistry   78 ( 11 ) 5579 - 5586  2013

     View Summary

    A rapid synthesis of thiophene-based TAK-779 analogues 1 is reported using a late-stage diversification strategy. At the end of the synthesis, the key building block 2, which was prepared in six steps from thiophene, was arylated regioselectively at the α-position directly with iodoarenes. Since 2 offers several reactive positions, various established catalyst systems were tested. It was found that Crabtree catalyst (an Ir catalyst) converted efficiently and selectively the thiophene system 2 into 2-aryl-substituted compounds 9. The direct C-H arylation of 2 with electron-rich iodoarenes led to high yields, whereas electron-deficient iodoarenes required longer reaction times for complete conversion. A small set of diverse amides 1 was synthesized by hydrolysis of 9 and subsequent HATU coupling with primary amines 4. © 2013 American Chemical Society.

    DOI PubMed

  • Aromatic C-H coupling with hindered arylboronic acids by Pd/Fe dual catalysts

    Kazuya Yamaguchi, Hiroki Kondo, Junichiro Yamaguchi, Kenichiro Itami

    CHEMICAL SCIENCE   4 ( 9 ) 3753 - 3757  2013

     View Summary

    An aerobic oxidative coupling of arenes/alkenes with arylboronic acids (C-H/C-B coupling) using catalytic Pd(II)-sulfoxide-oxazoline (sox) ligand and iron-phthalocyanine (FePc) has been developed. This dual catalyst system enables the synthesis of sterically hindered heterobiaryls and styrene derivatives under air without stoichiometric co-oxidants. Additionally, this chemistry demonstrated an advance toward an enantioselective biaryl coupling through C-H functionalization.

    DOI

  • Late-Stage C-H Bond Arylation of Spirocyclic sigma(1) Ligands for Analysis of Complementary sigma(1) Receptor Surface

    Christina Meyer, Dirk Schepmann, Shuichi Yanagisawa, Junichiro Yamaguchi, Kenichiro Itami, Bernhard Wuensch

    EUROPEAN JOURNAL OF ORGANIC CHEMISTRY   ( 30 ) 5972 - 5979  2012.10

     View Summary

    Direct CH bond arylation in the a- and beta-positions of spirocyclic thiophenes containing various functional groups (amine, ether, acetal, lactone) was accomplished. Selective phenylation in the a-position of the thiophene ring was achieved by using the catalytic system PdCl2/bipy/Ag2CO3. The introduction of phenyl moieties to the beta-position was performed with the catalytic system PdCl2/P[OCH(CF3)2]3/Ag2CO3. Even the five-membered lactone 10 with an electron-withdrawing carbonyl moiety directly attached to the thiophene ring was arylated. Spirocyclic thiophenes substituted with a phenyl moiety in position A (top position) or B (left position) display low nanomolar s1 affinities (e.g., 4a: Ki = 1.6 nM; 5a: Ki = 2.4 nM), indicating an additional hydrophobic pocket on the complementary s1 receptor protein. A phenyl moiety in position C (at the bottom position) is not tolerated by the s1 receptor (e.g., 12: Ki = 483 nM). However, an additional phenyl moiety in position A is able to compensate at least partially the unfavorable effects of the phenyl moiety in position C.

    DOI

  • Pd- and Cu-catalyzed C-H arylation of indazoles

    Keika Hattori, Kazuya Yamaguchi, Junichiro Yamaguchi, Kenichiro Itami

    TETRAHEDRON   68 ( 37 ) 7605 - 7612  2012.09

     View Summary

    The palladium- and copper-catalyzed C-H arylation reactions of 1H- and 2H-indazoles with haloarenes are described. A PdCl2/phen/Ag2CO3/K3PO4 catalytic system is effective for the C-H arylation of 1H- and 2H-indazoles with haloarenes, whereas a less expensive CuI/phen/LiOt-Bu catalytic system is applicable to the C H coupling of substituted 2H-indazoles and iodoarenes. The utility of newly developed catalyst was demonstrated in the rapid synthesis of YC-1 (an antitumor agent) and YD-3 (platelet anti-aggregating agent). These new reactions represent important direct functionalization tools of indazoles, well-known bioisosteres of pharmaceutically important indole core. (C) 2012 Elsevier Ltd. All rights reserved.

    DOI

  • Pd-Catalyzed Direct C-H Bond Functionalization of Spirocyclic sigma(1) Ligands: Generation of a Pharmacophore Model and Analysis of the Reverse Binding Mode by Docking into a 3D Homology Model of the sigma(1) Receptor

    Christina Meyer, Dirk Schepmann, Shuichi Yanagisawa, Junichiro Yamaguchi, Valentina Dal Col, Erik Laurini, Kenichiro Itami, Sabrina Pricl, Bernhard Wuensch

    JOURNAL OF MEDICINAL CHEMISTRY   55 ( 18 ) 8047 - 8065  2012.09

     View Summary

    To explore the hydrophobic binding region of the sigma(1) receptor protein, regioisomeric spirocyclic thiophenes 9-11 were developed as versatile building blocks. Regioselective alpha- and beta-arylation using the catalyst systems PdCl2/bipy/Ag2CO3 and PdCl2/P[OCH(CF3)(2)](3)/Ag2CO3 allowed the introduction of various aryl moieties at different positions in the last step of the synthesis. The increasing sigma(1) affinity in the order 4 &lt; 5/6 &lt; 7/8 indicates that the positions of the additional aryl moiety and the S atom in the spirocyclic thiophene systems control the sigma(1) affinity. The main features of the pharmacophore model developed for this class of sigma(1) ligands are a positive ionizable group, a H-bond acceptor group, two hydrophobic moieties, and one hydrophobic aromatic group. Docking of the ligands into a sigma(1) 3D homology model via molecular mechanics/Poisson-Boltzmann surface area calculations led to a very good correlation between the experimentally determined and estimated free energy of receptor binding. These calculations support the hypothesis of a reverse binding mode of ligands bearing the aryl moiety at the "top" (compounds 2, 3, 7, and 8) and "left" (compounds 4, 5, and 6) positions, respectively.

    DOI PubMed

  • Decarbonylative C-H Coupling of Azoles and Aryl Esters: Unprecedented Nickel Catalysis and Application to the Synthesis of Muscoride A

    Kazuma Amaike, Kei Muto, Junichiro Yamaguchi, Kenichiro Itami

    JOURNAL OF THE AMERICAN CHEMICAL SOCIETY   134 ( 33 ) 13573 - 13576  2012.08

     View Summary

    A nickel-catalyzed decarbonylative C-H biaryl coupling of azoles and aryl esters is described. The newly developed catalytic system does not require the use of expensive metal catalysts or silver- or copper-based stoichiometric oxidants. We have successfully applied this new C-H arylation reaction to a convergent formal synthesis of muscoride A.

    DOI PubMed

  • Nickel-Catalyzed C-H/C-O Coupling of Azoles with Phenol Derivatives

    Kei Muto, Junichiro Yamaguchi, Kenichiro Itami

    JOURNAL OF THE AMERICAN CHEMICAL SOCIETY   134 ( 1 ) 169 - 172  2012.01

     View Summary

    The first nickel-catalyzed C-H bond arylation of azoles with phenol derivatives is described. The new Ni(cod)(2)/dcype catalytic system is active for the coupling of various phenol derivatives such as esters, carbamates, carbonates, sulfamates, triflates, tosylates, and mesylates. With this C-H/C-O biaryl coupling, we synthesized a series of privileged 2-arylazoles, including biologically active alkaloids. Moreover, we demonstrated the utility of the present reaction for functionalizing estrone and quinine.

    DOI

  • Hindered biaryls by C-H coupling: bisoxazoline-Pd catalysis leading to enantioselective C-H coupling

    Kazuya Yamaguchi, Junichiro Yamaguchi, Armido Studer, Kenichiro Itami

    CHEMICAL SCIENCE   3 ( 6 ) 2165 - 2169  2012

     View Summary

    A new Pd-catalyzed C-H/C-B coupling of sterically hindered heteroarenes and arylboronic acids has been identified. The newly established Pd(OAc)(2)/bisoxazoline/TEMPO system not only enables the synthesis of sterically hindered heterobiaryls but also offers an opportunity for enantioselective biaryl coupling through C-H functionalization.

    DOI

  • C-H Bond Functionalization: Emerging Synthetic Tools for Natural Products and Pharmaceuticals

    Junichiro Yamaguchi, Atsushi D. Yamaguchi, Kenichiro Itami

    ANGEWANDTE CHEMIE-INTERNATIONAL EDITION   51 ( 36 ) 8960 - 9009  2012

    Book review, literature introduction, etc.  

     View Summary

    The direct functionalization of C-H bonds in organic compounds has recently emerged as a powerful and ideal method for the formation of carbon-carbon and carbon-heteroatom bonds. This Review provides an overview of C-H bond functionalization strategies for the rapid synthesis of biologically active compounds such as natural products and pharmaceutical targets. The ideal case: The direct functionalization of C-H bonds in organic compounds has recently emerged as a powerful and ideal method for the formation of carbon-carbon and carbon-heteroatom bonds. This Review provides an overview of C-H functionalization strategies for the rapid synthesis of biologically active compounds such as natural products and pharmaceutical targets. Copyright © 2012 WILEY-VCH Verlag GmbH &amp; Co. KGaA, Weinheim.

    DOI PubMed

  • Enantioselective Total Syntheses of (-)-Palau'amine, (-)-Axinellamines, and (-)-Massadines

    Ian B. Seiple, Shun Su, Ian S. Young, Akifumi Nakamura, Junichiro Yamaguchi, Lars Jorgensen, Rodrigo A. Rodriguez, Daniel P. O'Malley, Tanja Gaich, Matthias Koeck, Phil S. Baran

    JOURNAL OF THE AMERICAN CHEMICAL SOCIETY   133 ( 37 ) 14710 - 14726  2011.09

     View Summary

    Dimeric pyrrole-imidazole alkaloids represent a rich and topologically unique class of marine natural products. This full account will follow the progression of efforts that culminated in the enantioselective total syntheses of the most structurally ornate members of this family: the axinellamines, the massadines, and palau'amine. A bio-inspired approach capitalizing on the pseudo-symmetry of the members of this class is recounted, delivering a deschloro derivative of the natural product core. Next, the enantioselective synthesis of the chlorocyclopentane core featuring a scalable, catalytic, enantioselective Diels-Alder reaction of a 1-siloxydiene is outlined in detail. Finally, the successful divergent conversion of this core to each of the aforementioned natural products, and the ensuing methodological developments, are described.

    DOI PubMed

  • Synthesis of Bioactive Compounds through C-H Bond Functionalization

    YAMAGUCHI JUNICHIRO, ITAMI KENICHIRO

      53 ( 5 ) 293 - 297  2011.08

    CiNii

  • Oxidative C-H/C-H Coupling of Azine and Indole/Pyrrole Nuclei: Palladium Catalysis and Synthesis of Eudistomin U

    Atsushi D. Yamaguchi, Debashis Mandal, Junichiro Yamaguchi, Kenichiro Itami

    CHEMISTRY LETTERS   40 ( 6 ) 555 - 557  2011.06

     View Summary

    We have developed a palladium-catalyzed C-H/C-H coupling reaction of indoles or pyrroles with azine N-oxides. The reaction proceeds selectively at the C3 position of indoles/pyrroles and the C2 position of azine N-oxides. Furthermore, we have accomplished the synthesis of marine indole alkaloid eudistomin U by utilizing this newly developed C-H/C-H coupling reaction.

    DOI

  • Exploitation of an additional hydrophobic pocket of sigma(1) receptors: Late-stage diverse modifications of spirocyclic thiophenes by C-H bond functionalization

    Christina Meyer, Benedikt Neue, Dirk Schepmann, Shuichi Yanagisawa, Junichiro Yamaguchi, Ernst-Ulrich Wuerthwein, Kenichiro Itami, Bernhard Wuensch

    ORGANIC & BIOMOLECULAR CHEMISTRY   9 ( 23 ) 8016 - 8029  2011

     View Summary

    The hypothesis that the sigma(1) receptor will tolerate an additional aryl moiety in position 1 of the spirocyclic system was based on spirocyclic pyrazole derivatives, pharmacophore models of sigma(1) receptor ligands and DFT calculations. The strategy of introducing the aryl residue at the final step of the synthesis allowed the preparation of a large set of diverse ligands for the exploitation of the hydrophobic pocket of the sigma(1) receptor protein. The catalyst system PdCl2/2,2'-bipyridyl/Ag2CO3 is able to introduce various aryl groups onto the alpha-positions of spirocyclic thiophene derivatives 5 and 6 to afford the target aryl-appended spirocyclic thiophenes 3 and 4. Although the sigma(1) affinity of the 1-phenyl substituted spirocyclic thiophenes 3a and 4a is slightly reduced compared with the sigma(1) affinity of the non-arylated compounds 5 and 6, both compounds represent very potent sigma(1) receptor ligands (3a: K-i = 4.5 nM; 4a: K-i = 1.0 nM). This result indicates that an aryl moiety in position 1 is well tolerated by the sigma(1) receptor protein. The substitution pattern of the additional phenyl moiety has only weak effects on the sigma(1) affinity. Even ligands 3f and 4h with extended naphthyl residue show high sigma(1) affinity. However, decrease of sigma(1) affinity by extension of the p-system to a biphenylyl substituent (4j: K-i = 30 nM) indicates that the biphenylyl residue is too large for the primary hydrophobic binding pocket of the sigma(1) receptor.

    DOI PubMed

  • Total Synthesis of Palau&apos;amine

    Ian B. Seiple, Shun Su, Ian S. Young, Chad A. Lewis, Junichiro Yamaguchi, Phil S. Baran

    ANGEWANDTE CHEMIE-INTERNATIONAL EDITION   49 ( 6 ) 1095 - 1098  2010

    Book review, literature introduction, etc.  

     View Summary

    (Figure Presented) Worth the wait: The long anticipated total synthesis of palau&#039;amine has been accomplished by a route featuring highly chemoselective transformations, cascade reactions, and a remarkable transannular cyclization to secure the unprecedented trans-5,5 ring junction (shown in red). © 2010 Wiley-VCH Verlag GmbH &amp; Co. KGaA.

    DOI PubMed

  • Nickel-Catalyzed Biaryl Coupling of Heteroarenes and Aryl Halides/Triflates

    Jerome Canivet, Junichiro Yamaguchi, Ikuya Ban, Kenichiro Itami

    ORGANIC LETTERS   11 ( 8 ) 1733 - 1736  2009.04

     View Summary

    Ni-based catalytic systems for the arylation of heteroarenes with aryl halides and triflates have been established. Ni(OAc)(2)/bipy is a general catalyst for aryl bromides/iodides, and Ni(OAC)(2)/dppf is effective for aryl chlorides/triflates. Thiazole, benzothiazole, oxazole, benzoxazole, and benzimidazole are applicable as heteroarene coupling partners. A rapid synthesis of febuxostat, a drug for gout and hyperuricemia, is also demonstrated.

    DOI PubMed

  • Asymmetric Total Synthesis of a Natural Product Using Catalytic Enantioselective Stereoablative Reactions

    Junichiro Yamaguchi

    JOURNAL OF SYNTHETIC ORGANIC CHEMISTRY JAPAN   67 ( 2 ) 166 - 167  2009.02

     View Summary

    Catalytic enantioselective stereoablative reactions represent a unique approach to the preparation of enantioenriched materials, wherein a catalytic method destroys, at least temporarily, stereogenic elements of a molecule. This review introduces a recent example of novel approaches in asymmetric catalytic methods for stereoablation, as well as the use of a new stereoablative reaction in a concise synthesis of the marine diterpenoid (-)-cyanthiwigin F.

    DOI

  • Fe-Catalyzed Oxidative Coupling of Heteroarenes and Methylamines

    Masaki Ohta, Matthias P. Quick, Junichiro Yamaguchi, Bernhard Wuensch, Kenichiro Itami

    CHEMISTRY-AN ASIAN JOURNAL   4 ( 9 ) 1416 - 1419  2009

    DOI PubMed

  • Direct asymmetric alpha-amination of cyclic ketones catalyzed by siloxyproline

    Yujiro Hayashi, Seiji Aratake, Yoshinaga Imai, Kazuhiro Hibino, Qi-Yin Chen, Junichiro Yamaguchi, Tadafumi Uchimaru

    CHEMISTRY-AN ASIAN JOURNAL   3 ( 2 ) 225 - 232  2008

     View Summary

    trans-tert-Butyldimethylsiloxy-L-proline displays greater catalytic activity and affords higher enantioselectivity than the parent proline in the alpha-amination reaction of carbonyl compounds with azodicarboxylate. A quantum mechanical calculation reveals the structure of the transition state. In the presence of a catalytic amount of siloxyproline and water (3-9 equiv), alpha-amino carbonyl derivatives, which are important synthetic intermediates, are obtained in good yield and with excellent enantioselectivity.

    DOI PubMed

  • Determination by asymmetric total synthesis of the absolute configuration of lucilactaene, a cell-cycle inhibitor in p53-transfected cancer cells

    J Yamaguchi, H Kakeya, T Uno, M Shoji, H Osada, Y Hayashi

    ANGEWANDTE CHEMIE-INTERNATIONAL EDITION   44 ( 20 ) 3110 - 3115  2005

     View Summary

    (Chemical Equation Presented) A biomimetic pathway to lucilactaene (1) from NG-391 has been developed which involves stereoselective reactions under very mild conditions. It was demonstrated that 1 racemizes rapidly, and the conditions under which racemization occurs were elucidated. Lucilactaene (1) isolated under neutral conditions is racemic, which suggests that either the natural product is racemized rapidly in the mycelia, or racemic 1 is biosynthesized. © 2005 Wiley-VCH Verlag GmbH &amp; Co. KGaA.

    DOI PubMed

  • Direct proline-catalyzed asymmetric alpha-aminoxylation of aldehydes and ketones

    Y Hayashi, J Yamaguchi, T Sumiya, K Hibino, M Shoji

    JOURNAL OF ORGANIC CHEMISTRY   69 ( 18 ) 5966 - 5973  2004.09

    Book review, literature introduction, etc.  

     View Summary

    The direct proline-catalyzed asymmetric alpha-aminoxylation of aldehydes and ketones has been developed using nitrosobenzene as an oxygen source, affording alpha-anilinoxy-aldehydes and -ketones with excellent enantioselectivity. Reaction conditions have been optimized, and low temperature (-20 degreesC) was found to be a key for the successful alpha-aminoxylation of aldehydes, while slow addition of nitrosobenzene is essential for that of ketones. The scope of the reaction is presented.

    DOI PubMed

  • Direct proline-catalyzed asymmetric alpha-aminoxylation of ketones

    Y Hayashi, J Yamaguchi, T Sumiya, M Shoji

    ANGEWANDTE CHEMIE-INTERNATIONAL EDITION   43 ( 9 ) 1112 - 1115  2004

     View Summary

    Nitrosobenzene is the oxygen source in the direct catalytic enantioselective α-aminoxylation of ketones catalyzed by L-proline [Eq. (1)]. Versatile α-aminoxylated ketones are obtained in high yield and with excellent enantioselectivities.

    DOI PubMed

  • Direct proline catalyzed asymmetric alpha-aminooxylation of aldehydes

    Y Hayashi, J Yamaguchi, K Hibino, M Shoji

    TETRAHEDRON LETTERS   44 ( 45 ) 8293 - 8296  2003.11

     View Summary

    The direct catalytic enantioselective alpha-aminooxylation of aldehydes has been developed using nitrosobenzene as the oxygen source and L-proline as catalyst, affording versatile alpha-aminooxylated aldehydes in high yield with excellent enantioselectivities. (C) 2003 Elsevier Ltd. All rights reserved.

    DOI

  • The diastereoselective asymmetric total synthesis of NG-391, a neuronal cell-protecting molecule

    Y Hayashi, J Yamaguchi, M Shoji

    TETRAHEDRON   58 ( 49 ) 9839 - 9846  2002.12

     View Summary

    The stereocontrolled total synthesis of (+)-NG-391, a neuronal cell-protecting molecule, is described along with the determination of its absolute stereochemistry. The following reactions in this synthesis are particularly noteworthy: (1) The stereoselective construction of the conjugated (E,E,E,E,E)-pentaene from an (E,E,E)-alcohol using an IBX oxidation followed by stereoselective Horner-Emmons reaction. (2) The (E)-selective Knoevenagel condensation of a beta-ketonitrile with a chiral 2-alkoxyaldehyde prepared from (S)-malic acid. (3) A diastereoselective epoxidation. (C) 2002 Elsevier Science Ltd. All rights reserved.

    DOI

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Awards

  • Waseda research award 2019

    2020.03  

  • Lectureship Award (MEXT Grant-in-Aid for Scientific Research on Innovative Area, Japan)

    2019.10  

  • Prizes for Science and Technology from MEXT (Public Understanding Promotion Category)

    2019.05  

  • The Chemical Society of Japan Award for Merits for Chemical Education for 2017

    2018.03  

  • NISTEP award 2017

    2017.12  

  • FACS Distinguished Young Chemist Award

    2017.05  

  • The Young Scientists’ Prize from MEXT

    2017.03  

  • Asian Core Lectureship Award, Thailand

    2014  

  • Asian Core Lectureship Award, China

    2014  

  • Thieme Chemistry Journal Award

    2014   Thieme Chemistry Journal Award

  • Banyu Chemist Award 2013

    2013.11  

  • ITbM research award

    2013.10  

  • 化学コミュニケーション賞2012

    2013.03  

  • 日本化学会進歩賞

    2013.03  

  • 若い世代の特別講演会 特別講演証

    2012.03  

  • 天然物化学談話会奨励賞

    2011.07  

  • 有機合成化学協会研究企画賞

    2009.02  

  • 日本化学会学生講演賞

    2006  

  • 小玉科学賞

    2004  

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Research Projects

  • 炭素―水素結合の直接変換を鍵とする生物活性物質の合成

    Project Year :

    2008
     
     
     

  • C–H Bond Functionalization: Emerging Synthetic Technology for Natural Products and Drugs

    Project Year :

    2008
     
     
     

Specific Research

  • 芳香族エステルの脱酸素型変換反応の開発

    2021  

     View Summary

    パラジウム触媒存在下、芳香族エステルとアリールボロン酸からベンゾフェノン誘導体を合成した後、添加剤としてジフェニルホスフィンオキシドと還元剤を用いワンポットで加熱撹拌した。その結果、所望のベンジル化体と還元的マクマリーカップリングが進行したテトラアリールエタンが得られた。反応条件を精査したところ、ジアリールメタンおよびテトラアリールエタンをそれぞれ高収率で得られる条件を見いだした。中間体とボロン酸との鈴木―宮浦クロスカップリング反応およびFriedel–Crafts型反応[により、トリアリールメタンにも誘導できる。本反応は電子供与基や電子求引基をもつジアリールケトン、多環式化合物にも適用可能であり、種々の医薬品誘導体の合成にも成功した(計60種類)。

  • 化学コミュニケーション分子を利用した植物時計の機構解明

    2020  

     View Summary

    本研究では、植物CK1阻害剤として我々が発見した三種類の分子を武器に、サブタイプ選択性を向上させた新規阻害剤を創製し、植物概日時計制御におけるCK1 タンパク質の詳細な役割の解明を目指す。はじめに植物概日リズム調整剤PHA のSAR 研究と標的タンパク質の同定に着手した。また高活性な部分構造を組み合わせたハイブリッド体(AMI-331)が、PHA と比較して約100 倍の活性を示した。その結果、AMI-331 をもとにした分子プローブを合成し、プルダウンアッセイを行ったところCK選択性が格段に向上した。また、植物CK1 阻害剤PHA とB-AZ[6]の構造を基にin silico スクリーニングで見いだした化合物DB8およびDB9 の合成に成功した。

  • ヘテロ芳香環開環型フッ素化反応の開発

    2020  

     View Summary

    本研究は創薬を志向した斬新な不斉フッ素化反応を開発することを目的とした。ヘテロ原子―ヘテロ 原子結合(S‒N, O‒N, N‒N結合)を含むヘテロ芳香環を求核剤、フッ素化剤を求電子剤として 環変換反応によりヘテロ芳香環を「破壊」し新たな骨格へと転成させる。得られる生成物は、 (ヘテロ芳香環)―4級不斉炭素―極性官能基をすべて含む医薬品候補化合物頻出骨格である。 本特定課題において、あるヘテロ環に求電子的なフッ素化剤として知 られるsectfluor® をアセトニトリル中作用させると開環反応が進行し、フッ素化合物が得られることを見出した。様々な置換基を有する化合物にも適用可能であり、これまで基質が限られていたフッ素化反応に新手法という一石を投じることができた。

  • エステル転位反応の開発/Development of Ester Dance Reaction

    2019  

     View Summary

    芳香族化合物の官能基化はそれらの機能を十分に発揮するために必須な装飾である。従って、芳香族化合物の官能基化反応は有機合成化学において古くより検討が行われている。芳香族求電子置換反応や求核置換反応などにより、位置優先的・選択的に置換基を導入した置換芳香族化合物が合成できる。最近では触媒的な芳香族化合物の官能基化反応が研究され、例えば、触媒量の遷移金属存在下、炭素-水素結合を直裁的に変換する手法(芳香環C–H結合直接変換反応)の開発が盛んである。我々はごく最近、研究室で開発している「芳香族エステルの脱カルボニル型カップリング反応」反応開発中、思いがけず「触媒的エステルダンス反応」を発見した。本研究ではこの反応の最適化、基質一般性を検討した。

  • 汎用官能基切断型カップリング反応の開発

    2018  

     View Summary

    本研究では、安価なケミカルフィードストックが有する汎用官能基を切断し様々な求核剤とのカップリング反応を行う。具体的には①フェノール誘導体、②芳香族チオエステル、③芳香族カルボン酸誘導体、そして④芳香族ニトロ化合物を対象とした。。切断—置換反応の足がかりとなるのは触媒サイクルのあらゆる段階を促進する、基質に含まれる無痕跡配向基と精密にデザインされた配位子である。①ー④すべての官能基を活性化することに成功し、脱カルボニル型エーテル化反応・チオエーテル化反応、C-P結合形成、アルキル化反応を見いだした。分子内C-H結合も同様に活性化し、ジベンゾフラン誘導体も合成することに成功した。

  • マルチアレーン・アセン化合物のプログラム合成法の開発

    2016  

     View Summary

    芳香族化合物群は、機能性分子における最重要骨格のひとつである。特にアリール基で置換された芳香族化合物群は、光電子機能性材料や生体機能性材料に頻繁に見られる。導入するアリール基の性質に起因して分子全体の構造あるいは電子的性質は大きく変化するため、分子の機能を発現する上でアリール基は重要な役割を担っている。そのため、アリール基を芳香族化合物に自在に導入することが出来れば、分子の機能を自在に操ることが可能となる。我々は既にチオフェンやチアゾールが有するC–H結合を望みの位置かつ望みの様式でアリール基に変換することで、アリール化された5員環芳香族ヘテロ環の自在合成を可能としてた。また、得られた5員環からの環変換反応によりアリール基がすべて異なるヘキサアリールベンゼン、ヘキサアリールピリジンの合成を達成してた。さらに、アリール化された5員環ヘテロ芳香族化合物の環変換反応により、マルチアリール化アセン・ヘテロールの自在合成法を開発した。

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Syllabus

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