2024/05/21 更新

写真a

ヤマグチ ジュンイチロウ
山口 潤一郎
所属
理工学術院 先進理工学部
職名
教授
ホームページ

経歴

  • 2018年04月
    -
    継続中

    早稲田大学   理工学術院   教授

  • 2016年04月
    -
    2018年03月

    早稲田大学   理工学術院   准教授

  • 2012年04月
    -
    2016年03月

    名古屋大学准教授   大学院理学研究科   准教授

  • 2012年08月
    -
    2012年09月

    ドイツミュンスター大学客員准教授

  • 2008年08月
    -
    2012年03月

    名古屋大学理学研究科助教

  • 2007年04月
    -
    2008年07月

    スクリプス研究所化学科博士研究員

  • 2007年04月
    -
    2008年07月

    日本学術振興会海外特別研究員

  • 2004年04月
    -
    2007年03月

    日本学術振興会特別研究員(DC1)

▼全件表示

所属学協会

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    アメリカ化学会

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    近畿化学協会有機金属部会

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    有機合成化学協会

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    日本化学会

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    American Chemical Society

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    The Kinki Chemical Society, Japan

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    The Society of Synthetic Organic Chemistry, Japan

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    The Chemical Society of Japan

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研究分野

  • 有機合成化学

研究キーワード

  • 汎用官能基切断型カップリング

受賞

  • 早稲田大学リサーチアワード(国際研究発信力)

    2020年03月  

  • 新学術領域「精密反応場」レクチャシップアワード

    2019年10月  

  • 文部科学大臣表彰科学技術賞(理解増進部門)

    2019年05月  

  • 日本化学会第42回化学教育賞

    2018年03月  

  • 科学技術への顕著な貢献 2017(ナイスステップな研究者)

    2017年12月  

  • アジア化学連合(FACS)ディスティングィッシュ若手化学者賞

    2017年05月  

  • 文部科学大臣表彰若手科学者賞

    2017年03月  

  • Asian Core Lectureship Award, Thailand

    2014年  

  • Asian Core Lectureship Award, China

    2014年  

  • Thieme Chemistry Journal Award

    2014年   Thieme Chemistry Journal Award  

  • Banyu Chemist Award 2013

    2013年11月  

  • ITbM research award

    2013年10月  

  • 化学コミュニケーション賞2012

    2013年03月  

  • 日本化学会進歩賞

    2013年03月  

  • 若い世代の特別講演会 特別講演証

    2012年03月  

  • 天然物化学談話会奨励賞

    2011年07月  

  • 有機合成化学協会研究企画賞

    2009年02月  

  • 日本化学会学生講演賞

    2006年  

  • 小玉科学賞

    2004年  

▼全件表示

 

論文

  • Palladium-Catalyzed Synthesis of Bicyclic Derivatives from the Cyclization/1,4-Difunctionalization of Bromoarenes with Diazo Compounds

    Hiroki Kato, Yuki Fukuhara, Ryuya Miyazaki, Kei Muto, Junichiro Yamaguchi

    Asian Journal of Organic Chemistry   13 ( 2 )  2024年02月

     概要を見る

    A Pd-catalyzed cyclization/1,4-difunctionalization of bromoarenes bearing a carbon nucleophile with diazo compounds has been developed. The present reaction proceeds through a π-benzyl palladium intermediate, whose reactivity is a key for the remarkable 1,4-selectivity of this reaction, providing functionalized indans and tetralins.

    DOI

    Scopus

  • Concise Synthesis of (±)-Fortuneicyclidins and (±)-Cephalotine B Enabled by Pd-Catalyzed Dearomative Spirocyclization**

    Yota Uwabe, Kei Muto, Junichiro Yamaguchi

    Chemistry - A European Journal   29 ( 68 )  2023年12月

     概要を見る

    Total syntheses of C11-oxygenated Cephalotaxus alkaloids, fortuneicyclidins A and B, and cephalotine B, were achieved. The key for the synthesis is a Pd-catalyzed dearomative spirocyclization of bromofurans with N-tosylhydrazones, followed by acid-mediated tandem transformation to construct the tetracyclic skeleton with the C11-oxygen functional group. Chemo-selective and catalytic functional group conversions of the tetracyclic intermediate completed the synthesis of fortuneicyclidins and cephalotine B in 8 and 9 steps, respectively.

    DOI PubMed

    Scopus

    2
    被引用数
    (Scopus)
  • Regioselective Ring Opening of Oxetanes Enabled by Zirconocene and Photoredox Catalysis

    Eisuke Ota, Junichiro Yamaguchi, Kazuhiro Aida

    Synlett    2023年10月

     概要を見る

    Abstract

    Oxetanes are frequently utilized in organic synthesis, both as target products and as fairly reactive intermediates. Whereas ring cleavage of oxetanes through polar mechanisms has been extensively investigated, their radical-based counterparts remain underexplored. We used zirconocene and photoredox catalysis to open an oxetane ring in a radical manner. In our protocol, the reaction selectively delivers the more-substituted alcohols via putative less-stable radicals. This method not only affords the corresponding hydrogenated products, but also provides unique benzylidene acetal products.

    DOI

    Scopus

    1
    被引用数
    (Scopus)
  • A Small-Molecule Modulator Affecting the Clock-Associated PSEUDO-RESPONSE REGULATOR 7 Amount

    Takahiro N. Uehara, Saori Takao, Hiromi Matsuo, Ami N. Saito, Eisuke Ota, Azusa Ono, Kenichiro Itami, Toshinori Kinoshita, Takafumi Yamashino, Junichiro Yamaguchi, Norihito Nakamichi

    PLANT AND CELL PHYSIOLOGY    2023年09月

     概要を見る

    Circadian clocks are biological timekeeping systems that coordinate genetic, metabolic and physiological behaviors with the external day-night cycle. The clock in plants relies on the transcriptional-translational feedback loops transcription-translation feedback loop (TTFL), consisting of transcription factors including PSUEDO-RESPONSE REGULATOR (PRR) proteins, plant lineage-specific transcriptional repressors. Here, we report that a novel synthetic small-molecule modulator, 5-(3,4-dichlorophenyl)-1-phenyl-1,7-dihydro-4H-pyrazolo[3,4-d] pyrimidine-4,6(5H)-dione (TU-892), affects the PRR7 protein amount. A clock reporter line of Arabidopsis was screened against the 10,000 small molecules in the Maybridge Hitfinder 10K chemical library. This screening identified TU-892 as a period-lengthening molecule. Gene expression analyses showed that TU-892 treatment upregulates CIRCADIAN CLOCK-ASSOCIATED 1 (CCA1) mRNA expression. TU-892 treatment reduced the amount of PRR7 protein, a transcriptional repressor of CCA1. Other PRR proteins including TIMING OF CAB EXPRESSION 1 were altered less by TU-892 treatment. TU-892-dependent CCA1 upregulation was attenuated in mutants impaired in PRR7. Collectively, TU-892 is a novel type of clock modulator that reduces the levels of PRR7 protein.

    DOI

    Scopus

  • 植物概日時計制御分子の開発

    Ami N. Saito, Eisuke Ota, Norihito Nakamichi, Junichiro Yamaguchi

    Journal of Synthetic Organic Chemistry, Japan   81 ( 7 ) 718 - 730  2023年07月

    DOI

    Scopus

  • Pd-Catalyzed Denitriative Intramolecular Mizoroki–Heck Reaction

    Kitty K. Asahara, Kei Muto, Junichiro Yamaguchi

    Chemistry Letters    2023年03月

    DOI

    Scopus

    1
    被引用数
    (Scopus)
  • Chlorine Atom Transfer of Unactivated Alkyl Chlorides Enabled by Zirconocene and Photoredox Catalysis

    Toshimasa Okita, Kazuhiro Aida, Keisuke Tanaka, Eisuke Ota, Junichiro Yamaguchi

    Precision Chemistry    2023年02月  [査読有り]

    DOI

    Scopus

    7
    被引用数
    (Scopus)
  • Chloroacetyl boronate N-tosylhydrazone as a versatile synthetic building block

    Ryuya Miyazaki, Kei Muto, Junichiro Yamaguchi

    Chemical Communications    2023年

     概要を見る

    Chloroacetyl boronate N-tosylhydrazone (CABT) has been synthesized as a reagent to generate a diverse range of molecular skeletons. CABT can undergo a series of transformations involving nucleophilic substitution of the chloride and coupling of the N-tosylhydrazones, followed by boryl group functionalization. We further demonstrated that this CABT reagent could enable a diversity-oriented synthesis.

    DOI PubMed

    Scopus

  • Aryl sulfide synthesis via aryl exchange reaction

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

    Trends in Chemistry   5 ( 1 ) 102 - 103  2023年01月

    DOI

    Scopus

    1
    被引用数
    (Scopus)
  • Structure-Function Study of a Novel Inhibitor of Cyclin-Dependent Kinase C in Arabidopsis

    Ami N Saito, Akari E Maeda, Tomoaki T Takahara, Hiromi Matsuo, Michiya Nishina, Azusa Ono, Katsuhiro Shiratake, Michitaka Notaguchi, Takeshi Yanai, Toshinori Kinoshita, Eisuke Ota, Kazuhiro J Fujimoto, Junichiro Yamaguchi, Norihito Nakamichi

    Plant and Cell Physiology   63 ( 11 ) 1720 - 1728  2022年08月  [査読有り]

     概要を見る

    Abstract

    The circadian clock, an internal time-keeping system with period of about 24 h, coordinates many physiological processes with the day-night cycle. We previously demonstrated that BML-259 (N-(5-Isopropyl-2-thiazolyl) phenylacetamide), a small molecule with mammal CYCLIN DEPENDENT KINASE 5 (CDK5)/ CDK2 inhibition activity, lengthens Arabidopsis thaliana (Arabidopsis) circadian clock periods. BML-259 inhibits Arabidopsis CDKC kinase, which phosphorylates RNA polymerase II in the general transcriptional machinery. To accelerate our understanding of the inhibitory mechanism of BML-259 on CDKC, we performed structure-function studies of BML-259 using circadian period lengthening activity as an estimation of CDKC inhibitor activity in vivo. The presence of a thiazole ring is essential for period lengthening activity, whereas acetamide, isopropyl, and phenyl groups can be modified without effect. BML-259 analogue TT-539, as known a mammal CDK5 inhibitor, did not lengthen the period nor did it inhibit Pol II phosphorylation. TT-361, an analogue having a thiophenyl ring instead of a phenyl ring, possesses stronger period lengthening activity and CDKC;2 inhibitory activity than BML-259. In silico ensemble docking calculations using Arabidopsis CDKC;2 obtained by a homology modeling indicated that the different binding conformations between these molecules and CDKC;2 explains the divergent activities of TT539 and TT361.

    DOI

    Scopus

    3
    被引用数
    (Scopus)
  • Synthesis and Properties of Pyridine-Fused Triazolylidene–Palladium: Catalyst for Cross-Coupling Using Chloroarenes and Nitroarenes

    Keiichiro Iizumi, Keito P. Nakayama, Kenta Kato, Kei Muto, Junichiro Yamaguchi

    The Journal of Organic Chemistry    2022年08月

    DOI

    Scopus

    4
    被引用数
    (Scopus)
  • Identification of α-Synuclein Proaggregator: Rapid Synthesis and Streamlining RT-QuIC Assays in Parkinson’s Disease

    Fumito Takada, Takahito Kasahara, Kentaro Otake, Takamitsu Maru, Masanori Miwa, Kei Muto, Minoru Sasaki, Yoshihiko Hirozane, Masato Yoshikawa, Junichiro Yamaguchi

    ACS Medicinal Chemistry Letters   13 ( 9 ) 1421 - 1426  2022年08月

    DOI

    Scopus

    2
    被引用数
    (Scopus)
  • Decarbonylative Reductive Coupling of Aromatic Esters by Nickel and Palladium Catalyst

    Yunfei Peng, Ryota Isshiki, Kei Muto, Junichiro Yamaguchi

    Chemistry Letters   51 ( 7 ) 749 - 753  2022年07月

    DOI

    Scopus

  • Pd-Catalyzed 1,4-Carboamination of Bicyclic Bromoarenes with Diazo Compounds and Amines

    Qikun Wu, Kei Muto, Junichiro Yamaguchi

    Organic Letters   24 ( 23 ) 4129 - 4134  2022年06月

    DOI

    Scopus

    7
    被引用数
    (Scopus)
  • Chemical biology to dissect molecular mechanisms underlying plant circadian clocks

    Norihito Nakamichi, Junichiro Yamaguchi, Ayato Sato, Kazuhiro J Fujimoto, Eisuke Ota

    New Phytologist    2022年06月

    DOI

    Scopus

    7
    被引用数
    (Scopus)
  • Palladium-Catalyzed Tandem Ester Dance/Decarbonylative Coupling Reactions

    Masayuki Kubo, Naomi Inayama, Eisuke Ota, Junichiro Yamaguchi

    Organic Letters   24 ( 21 ) 3855 - 3860  2022年06月  [査読有り]

     概要を見る

    "Dance reaction" on the aromatic ring is a powerful method in organic chemistry to translocate functional groups on arene scaffolds. Notably, dance reactions of halides and pseudohalides offer a unique platform for the divergent synthesis of substituted (hetero)aromatic compounds when combined with transition-metal-catalyzed coupling reactions. Herein, we report a tandem reaction of ester dance and decarbonylative coupling enabled by palladium catalysis. In this reaction, 1,2-translocation of the ester moiety on the aromatic ring is followed by decarbonylative coupling with nucleophiles to enable the installation of a variety of nucleophiles at the position adjacent to the ester in the starting material.

    DOI PubMed

    Scopus

    3
    被引用数
    (Scopus)
  • Catalytic reductive ring opening of epoxides enabled by zirconocene and photoredox catalysis

    Kazuhiro Aida, Marina Hirao, Aiko Funabashi, Natsuhiko Sugimura, Eisuke Ota, Junichiro Yamaguchi

    Chem    2022年05月

    DOI

    Scopus

    14
    被引用数
    (Scopus)
  • Phosphorylation of RNA Polymerase II by CDKC;2 Maintains the Arabidopsis Circadian Clock Period.

    Takahiro N Uehara, Takashi Nonoyama, Kyomi Taki, Keiko Kuwata, Ayato Sato, Kazuhiro J Fujimoto, Tsuyoshi Hirota, Hiromi Matsuo, Akari E Maeda, Azusa Ono, Tomoaki T Takahara, Hiroki Tsutsui, Takamasa Suzuki, Takeshi Yanai, Steve A Kay, Kenichiro Itami, Toshinori Kinoshita, Junichiro Yamaguchi, Norihito Nakamichi

    Plant & cell physiology   63 ( 4 ) 450 - 462  2022年01月  [国内誌]

     概要を見る

    The circadian clock is an internal timekeeping system that governs about 24 h biological rhythms of a broad range of developmental and metabolic activities. The clocks in eukaryotes are thought to rely on lineage-specific transcriptional-translational feedback loops (TTFLs). However, the mechanisms underlying the basic transcriptional regulation events for clock function have not yet been fully explored. Here, through a combination of chemical biology and genetic approaches, we demonstrate that phosphorylation of RNA polymerase II by CYCLIN DEPENDENT KINASE C; 2 (CDKC;2) is required for maintaining the circadian period in Arabidopsis. Chemical screening identified BML-259, the inhibitor of mammalian CDK2/CDK5, as a compound lengthening the circadian period of Arabidopsis. Short term BML-259 treatment resulted in decreased expression of most clock-associated genes. Development of a chemical probe followed by affinity proteomics revealed that BML-259 binds to CDKC;2. Loss-of-function mutations of cdkc;2 caused a long period phenotype. In vitro experiments demonstrated that the CDKC;2 immunocomplex phosphorylates the C-terminal domain (CTD) of RNA polymerase II, and BML-259 inhibits this phosphorylation. Collectively, this study suggests that transcriptional activity maintained by CDKC;2 is required for proper period length, which is an essential feature of the circadian clock in Arabidopsis.

    DOI PubMed

    Scopus

    9
    被引用数
    (Scopus)
  • Ring-opening fluorination of bicyclic azaarenes

    Masaaki Komatsuda, Ayane Suto, Hiroki Kondo, Hiroyuki Takada, Kenta Kato, Bunnai Saito, Junichiro Yamaguchi

    Chemical Science   13 ( 3 ) 665 - 670  2022年

     概要を見る

    A ring-opening fluorination of bicyclic azaarenes was developed. Although this overall transformation can be classified as an electrophilic fluorination of aromatics, it is a novel type of fluorination that results in construction of tert-C–F bonds.

    DOI

    Scopus

    10
    被引用数
    (Scopus)
  • Unified Synthesis of Multiply Arylated Alkanes by Catalytic Deoxygenative Transformation of Diarylketones

    Miki B. Kurosawa, Kenta Kato, Kei Muto, Junichiro Yamaguchi

    Chemical Science   13 ( 36 ) 10743 - 10751  2022年

     概要を見る

    A deoxygenative transformation of diarylketones leading to multiply arylated alkanes was developed. Diarylketones were reacted with diphenylphosphine oxide resulting in a phospha-Brook rearrangement, followed by palladium-catalyzed cross-couplings or a Friedel–Crafts...

    DOI

    Scopus

    6
    被引用数
    (Scopus)
  • 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年08月

     概要を見る

    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

    Scopus

    16
    被引用数
    (Scopus)
  • 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年07月

     概要を見る

    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

    Scopus

    49
    被引用数
    (Scopus)
  • 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年01月

     概要を見る

    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年09月

     概要を見る

    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

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    74
    被引用数
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  • 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年07月  [査読有り]

    DOI

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    15
    被引用数
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  • 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年07月

     概要を見る

    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

    Scopus

    7
    被引用数
    (Scopus)
  • Ester dance reaction on the aromatic ring

    Kaoru Matsushita, Ryosuke Takise, Kei Muto, Junichiro Yamaguchi

    Science Advances   6 ( 28 ) eaba7614 - eaba7614  2020年07月  [査読有り]

     概要を見る

    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

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    23
    被引用数
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  • 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年06月

    DOI

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    13
    被引用数
    (Scopus)
  • 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年05月  [査読有り]

    DOI

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    22
    被引用数
    (Scopus)
  • 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年04月  [査読有り]

    DOI

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    28
    被引用数
    (Scopus)
  • 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年04月  [査読有り]

    DOI

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    35
    被引用数
    (Scopus)
  • 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年03月  [査読有り]

    DOI

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    23
    被引用数
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  • Synthesis of Decaarylanthracene with Nine Different Substituents

    Asako, T., Suzuki, S., Tanaka, S., Ota, E., Yamaguchi, J.

    Journal of Organic Chemistry   85 ( 23 ) 15437 - 15448  2020年  [査読有り]

     概要を見る

    A synthesis of decaarylanthracene with nine different substituents has been accomplished by a coupling/ring-transformation strategy. The oxidation of tetraarylthiophenes with four different substituents to the corresponding thiophene S-oxides and a [4 + 2] cycloaddition with a double benzyne precursor afforded a multiply arylated naphthalene derivative. Subsequently, the naphthalene derivative was converted into a naphthalyne, and then a [4 + 2] cycloaddition of another thiophene S-oxide provided decaarylanthracenes with nine different aryl groups.

    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年

     概要を見る

    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

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    13
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  • 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年  [査読有り]

     概要を見る

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

    DOI

    Scopus

    24
    被引用数
    (Scopus)
  • Pd-Catalyzed Alkenyl Thioether Synthesis from Thioesters and N-Tosylhydrazones

    Kota Ishitobi, Kei Muto, Junichiro Yamaguchi

    ACS Catalysis   9 ( 12 ) 11685 - 11690  2019年12月  [査読有り]

    DOI

    Scopus

    34
    被引用数
    (Scopus)
  • 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年12月  [査読有り]

    DOI PubMed

    Scopus

    17
    被引用数
    (Scopus)
  • Pd-Catalyzed Dearomative Three-Component Reaction of Bromoarenes with Diazo Compounds and Allylborates

    Komatsuda Masaaki, Kato Hiroki, Muto Kei, Yamaguchi Junichiro

    ACS CATALYSIS   9 ( 10 ) 8991 - 8995  2019年10月  [査読有り]

    DOI

    Scopus

    36
    被引用数
    (Scopus)
  • Structure-function study of a novel inhibitor of the casein kinase 1 family in Arabidopsis thaliana.

    Saito AN, Matsuo H, Kuwata K, Ono A, Kinoshita T, Yamaguchi J, Nakamichi N

    Plant direct   3 ( 9 ) e00172  2019年09月  [査読有り]  [国際誌]

    DOI PubMed

    Scopus

    13
    被引用数
    (Scopus)
  • Casein kinase 1 family regulates PRR5 and TOC1 in the Arabidopsis circadian clock.

    Uehara TN, Mizutani Y, Kuwata K, Hirota T, Sato A, Mizoi J, Takao S, Matsuo H, Suzuki T, Ito S, Saito AN, Nishiwaki-Ohkawa T, Yamaguchi-Shinozaki K, Yoshimura T, Kay SA, Itami K, Kinoshita T, Yamaguchi J, Nakamichi N

    Proceedings of the National Academy of Sciences of the United States of America   116 ( 23 ) 11528 - 11536  2019年06月  [査読有り]  [国際誌]

    DOI PubMed

    Scopus

    64
    被引用数
    (Scopus)
  • 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年06月  [査読有り]

    DOI

    Scopus

    39
    被引用数
    (Scopus)
  • 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年02月

     概要を見る

    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年01月  [査読有り]  [国際誌]

    DOI PubMed

    Scopus

    84
    被引用数
    (Scopus)
  • 45 C-Hアリール化反応を駆使したdragmacidin Dの全合成(口頭発表の部)

    山口 潤一郎, マンダル デバシス, 山口 敦史, 伊丹 健一郎

    天然有機化合物討論会講演要旨集   ( 53 ) 265 - 270  2011年09月

     概要を見る

    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

  • 37 Axinellamine A,Bの全合成(口頭発表の部)

    山口 潤一郎, Baran Phil S.

    天然有機化合物討論会講演要旨集   ( 50 ) 245 - 250  2008年09月

     概要を見る

    Dimeric pyrrole alkaloids, such as the axinellamines A and B (1), palau'amine (2) and the massadines (3) are marine derived natural products that represent a great opportunity to advance fundamental chemical synthesis. They bear as structural features a highly functionalized cyclopentane that is spiroannulated upon a guanidine unit, a second incorporation of a guanidine group within another ring framework, as well as one or two pyrrole moieties. To confirm the structures of this rare and peculiar group of natural products, many well-known synthetic organic chemists worldwide have embarked on their total synthesis. By considering a biosynthetic hypothesis, we reasoned that the syntheses of 1-3 should be feasible through an intermediate such as pre-axinellamines (4 and 5). As a result, we achieved the synthesis of an oxidative precursor to 4, namely 1,9-dideoxy-pre-axinellamine (9), via a tandem dehydration-chlorination event and direct incorporations of the two guanidine units as key steps in the 19-step synthetic accomplishment. Moreover, starting from an intermediate produced en route to 9, an oxidative ring-closing event of an intramolecular guanidine followed by a silver picolinate-catalyzed, novel C-H oxidation reaction that activated one of the guanidine units at the α position, allowed the achievement of the first total synthesis of axinellamines A and B.

    DOI CiNii

  • P-62 Panepophenanthrinの不斉全合成及びその構造活性相関(ポスター発表の部)

    林 雄二郎, 松澤 正芳, 山口 潤一郎, 庄司 満, 掛谷 秀昭, 小野瀬 利恵, 長田 裕之

    天然有機化合物討論会講演要旨集   ( 49 ) 661 - 666  2007年08月

     概要を見る

    The asymmetric total synthesis of (+)-panepophenanthrin (1), an inhibitor of ubiquitin-activating enzyme (E1), has been accomplished using proline-catalyzed asymmetric a-aminoxylation and the biomimetic Diels-Alder reaction as key steps. Asymmetric α-aminoxylation of 1,4-cyclohexanedione monoethylene ketal (6) in the presence of D-proline with nitrosobenzene gave (S)-α-aminoxylated cyclohexanone (5). After several diastereoselective reactions, the key intermediate 4 was obtained. The monomer 2 was synthesized by Stille coupling reaction of 4 with vinyl stannane 14, followed by removal of the silyl protecting group. The biomimetic Diels-Alder reaction of the monomer 2 was found to proceed efficiently under neat condition or in water. The investigation of the biological properties of new derivatives of (+)-panepophenanthrin (1) enabled us to develop new cell-permeable E1 inhibitors, RKTS-80 (21), -81 (22), and -82 (23).

    DOI CiNii

  • P-538 TOTAL SYNTHESIS OF PANEPOPHENANTHRIN AND BIOLOGICAL ACTIVITIES OF ITS DERIVATIVES

    Matsuzawa Masayoshi, Yamaguchi Junichiro, Shoji Mitsuru, Kakeya Hideaki, Osada Hiroyuki, Hayashi Yujiro

    International Symposium on the Chemistry of Natural Products   2006   "P - 538"  2006年07月

    DOI CiNii

  • 98(P-30) プロリンを用いた不斉触媒α-アミノオキシ化反応を鍵反応とするfumagillin,RK-805,FR65814の効率的全合成(ポスター発表の部)

    山口 潤一郎, 角谷 龍展, 日比野 和浩, 庄司 満, 掛谷 秀昭, 長田 裕之, 林 雄二郎

    天然有機化合物討論会講演要旨集   ( 46 ) 563 - 568  2004年10月

     概要を見る

    Fumagillin, TNP-470, fumagillol, RK-805 are angiogenesis inhibitors and are promising lead compounds for the treatment of angiogenesis-related diseases such as cancer and rheumatoid arthritis, while FR65814 is a structurally similar immunosuppressant. Structurally these compounds possess a cyclohexane framework, two epoxides and five or six contiguous chiral centers, three or four of which are on the cyclohexane ring. Because of their novel structure and important biological properties, these compounds have proved attractive targets for many research groups, and several total syntheses have been accomplished, among them pioneering work of Corey. We will disclose a concise, flexible and highly diastereoselective asymmetric total syntheses of RK-805, fumagillol and FR65814 using our recently developed proline mediated α-aminoxylation of carbonyl compounds as a key step. The initial aminoxylation controls the absolute and relative stereochemistry of the subsequently generated chiral centers formed by the following noteworthy diastereoselective transformations: 1) A highly diastereoselective formation of bis-silyl cyanide involving kinetic discrimination. 2) A diastereoselective Michael reaction by the use of vinyl zincate. 3) A stereoselective epoxidation 4) The importance of the order of the two epoxidations for the high diastereoselectivity. 5) A stereoselective reduction.

    DOI CiNii

  • 14 新規血管新生阻害剤azaspireneの全合成(口頭発表の部)

    庄司 満, 山口 新平, 向山 貴祐, 五東 弘昭, 山口 潤一郎, 浅見 行弘, 掛谷 秀昭, 長田 裕之, 林 雄二郎

    天然有機化合物討論会講演要旨集   ( 45 ) 79 - 84  2003年09月

     概要を見る

    Pseurotin A, isolated in 1976, inhibits chitin synthase and also induces cell differentiation of PC12 cells, while azaspirene, isolated in 2002 by Kakeya and Osada et al., is an angiogenesis inhibitor, and attracted much attention as a lead of a drug for the treatment of cancer. As they both contain a novel, highly-substituted and oxygenated 1-oxa-7-azaspiro[4.4]non-2-ene-4,6-dione skeleton with three continuous chiral centers, their total syntheses are a challenge. We have synthesized pseurotin A and azaspirene from the same key elaborated ketone intermediate. The ketone was stereoselectively synthesized by the following key reactions: a MgBr_2・OEt_2-mediated Mukaiyama aldol reaction affords the desired syn-aldol in good yield with high selectivity. A NaH-promoted, intramolecular cyclization of a non-activated alkynylamide provides (Z)-benzylidene-γ-lactam. The aldol condensation proceeds smoothly between a side chain aldehyde and the ketone containing functionalized γ-lactam moiety without protection of tert-alcohol and amide functionalities. In the synthesis of pseurotin A, introduction of the benzoyl group by the selective oxidation of a benzylidene moiety with dimethyldioxirane (DMD) was successfully performed. In the synthesis of azaspirene, we found that the order of the last two reactions is very important because the reversed reaction sequence afforded a racemic azaspirene. By this total synthesis, the absolute stereochemistry of azaspirene has been determined.

    DOI CiNii

▼全件表示

共同研究・競争的資金等の研究課題

  • 結合交換反応の開発と機械学習最適化

    日本学術振興会  科学研究費助成事業

    研究期間:

    2021年09月
    -
    2026年03月
     

    山口 潤一郎

     概要を見る

    本研究は、申請者らが見いだした異種結合交換反応(アリール交換反応)に適用可能な芳香環の拡大、さらに多種な結合交換が可能な触媒開発に着手する。具体的には、エステル・ニトロ基・ケトン・エーテル・ニトリルなどの不活性結合を同時に活性化可能な触媒を用いた結合交換反応により安価で入手容易な化合物から高付加価値の化合物を合成する。さらに、最も高反応性官能基であるハロゲンを残したまま不活性結合を活性化し得る反応系の探索に挑戦する。触媒設計と適用できる化合物群の選定は結合解離エネルギーと触媒構造の適切なパラメータ化を用いて機械学習によって得られた知見を最短の最適化法として駆使する。
    本年度は、関連する反応開発研究に着手し、独自に開発したニッケル触媒(Ni/dcypt)と芳香環交換反応という概念を用いて、新たな芳香族スルフィド合成法の開発に成功した。取扱いが容易な無臭の芳香族スルフィドをスルフィド化剤として使おうというユニークな発想のもとに生まれた新反応である。今回の研究により、医薬品などを含む40種類以上の化合物を様々な芳香族スルフィドに変換可能であることが分かっており、悪臭問題を解決できる斬新な芳香族スルフィド合成法を提供することとなる。
    さらには、本研究から派生した、エステル同士のカップリング反応、ジアリールケトンの脱酸素的カップリング反応、エステルダンス反応の拡張にも成功した。

  • デジタル化による高度精密有機合成の新展開

    日本学術振興会  科学研究費助成事業

    研究期間:

    2021年09月
    -
    2026年03月
     

    大嶋 孝志, 小池 隆司, 笹野 裕介, 高須 清誠, 安田 誠, 山口 潤一郎, 菅 誠治, 跡部 真人, 外輪 健一郎, 滝澤 忍, 椴山 儀恵, 矢島 知子, 宮尾 知幸, 小島 諒介, 武田 和宏, 松原 誠二郎, 矢田 陽

  • ヘテロ芳香環開環型フッ素化反応の開発

    日本学術振興会  科学研究費助成事業

    研究期間:

    2021年07月
    -
    2023年03月
     

    山口 潤一郎

     概要を見る

    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する。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た開環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。
    本研究では、ピラゾロ[1,5-a]ピリジンをはじめとする二環式アザアレーンおよびイゾオキサゾールなどのヘテロ芳香族化合物にSelectfluorを作用させることで芳香環開環型フッ素化が進行することを見いだした。本反応では、まずヘテロ芳香環が求電子的フッ素化剤と反応することで、フッ素が導入されたカチオン中間体を生じる。その後、脱プロトンおよび窒素&#8211;窒素/窒素-酸素結合が開裂することで開環型フッ素化体を与える。本反応は、形式的には芳香族化合物が求核剤であるものの、得られるフッ素化合物は芳香族フッ化物ではなく第三級フッ素化合物を与える新形式のフッ素化反応である。本反応は広範な二環式アザアレーンおよびイソオキサゾールに適用可能であり、医薬品誘導体などの合成終盤での変換も可能であった。さらに、得られたフッ素化体の誘導体化により、多様な含フッ素骨格を合成できた。

  • 脱カルボニル型変換反応の非線形展開:転位・脱酸素・メタセシス

    日本学術振興会  科学研究費助成事業

    研究期間:

    2019年04月
    -
    2022年03月
     

    山口 潤一郎

     概要を見る

    本研究は、我々が見出した芳香族化合物の脱カルボニル型カップリング反応の非線形展開を目指した触媒反応開発を行った。具体的には、エステルダンス(転移)反応、脱酸素型反応、 結合交換反応(メタセシス反応)という高難度反応開発に着手し、それらを実現した。各反応の進行には結合を活性化できる触媒が必須であり、いずれもパラジウムもしくはニッケル触媒とdcyptもしくはdcypeという電子豊富で嵩高い二座配位子の利用が効果的であった。

  • 多置換ヘテロール合成法によるヘテロ中分子の高効率合成

    日本学術振興会  科学研究費助成事業

    研究期間:

    2018年04月
    -
    2020年03月
     

    山口 潤一郎

     概要を見る

    芳香族置換基で置換された芳香族化合物は、有機材料、医薬品や天然物など、多岐にわたる機能性分子にみられる最重要分子骨格である。そのため、芳香環に対する自在な多置換基導入法の開発は、我々に革新的な機能性分子を創出する好機を与える。しかし、対称性の高い芳香族化合物に対し、位置選択的に望みの置換基を導入する方法は限られており、全て異なる芳香族置換基で置換されたベンゼン、ナフタレン、アントラセンの合成例はなかった。
    一方で我々は、5員環ヘテロ芳香族化合物の、C-H官能基化反応を含むカップリング反応と環変換反応を利用した、マルチアリール芳香族化合物のプログラム合成法を確立している。本合成法により、望みのアリール基の芳香環への自在な導入が可能となり、全てのアリール基の異なるヘキサアリールベンゼン(HAB)をはじめ、オクタアリールナフタレン(OAN)などのアセン類、その他ヘテロ芳香族化合物4)の合成に成功した。最近、この合成戦略を拡張して、9つの異なるアリール基を有するデカアリールアントラセン(DAA)の合成を達成した。また研究計画に記載のあった、ペンタアリールカルバゾールの合成に着手した。2-ブロモチオフェンを出発物質とし、逐次的なカップリング反応とチオフェンの酸化、チオフェン2位の芳香族置換基上へのイナミド部位の導入、続く分子内[4+2]付加環化反応によって、テトラアリールカルバゾールを合成した。その後、カルバゾールの窒素原子を芳香族求核置換反応によってアリール化することで、全てのアリール基が異なるペンタアリールカルバゾールの合成に成功した。本手法は、様々なアリール基で高度に置換されたカルバゾールを位置選択的に合成できる。

  • 芳香族化合物の触媒的官能基転位反応の開発

    日本学術振興会  科学研究費助成事業

    研究期間:

    2018年04月
    -
    2020年03月
     

    山口 潤一郎

     概要を見る

    芳香族カルボン酸誘導体は市販試薬や合成中間体として頻繁に見られる合成化学におけるユビキタス構造体である。芳香族カルボン酸誘導体は非常に安価であり、複素環合成法においては、原料にカルボン酸誘導体が用いられ、合成後の芳香環上にカルボン酸、およびエステル基は保持される。それらを他の官能基に変換することなく、直接、炭素骨格やヘテロ原子を含む化合物へ変換することは、工程数を低減させるのみならず、合成戦略を一新できる可能性がある。我々は芳香族カルボン酸誘導体の1つである芳香族エステルを標的として、ニッケル触媒を用いた脱カルボニル型反応を世界に先駆けて報告した。本年度は、エステルの非線形型の変換反応として、転移(メタセシス反応)、脱酸素型カップリング反応、エステルダンス反応という3つの新形式の反応を見いだすことに成功した。
    脱酸素型カップリング反応:以前、ニッケル触媒存在下、芳香族エステルを用いた有機リン化合物との脱カルボニル型C-P結合形成反応を開発した。この反応では芳香族エステルがアリール化剤として機能し、対応する芳香族リン化合物が得られる。一方我々は、用いる金属触媒をパラジウムへと変えることで、芳香族エステルがベンジル化剤としてはたらき、ベンジルリン化合物が得られることを見いだした。本反応はパラジウム/dcypt、添加剤としてギ酸ナトリウムを用いることで効率的に進行する。
    エステルダンス反応:パラジウム/dcypt触媒を用いることで、芳香族エステルのエステル骨格を結合位置のみ変えて、となりの炭素上に移動(1,2-転移)させる「エステルダンス反応」が進行することを見出した。有機化合物に頻出する構造の一つであるエステル骨格を芳香環上で1,2-転移させる反応は本例が初めてである。また、遷移金属触媒を用いることで効率的に進行する芳香族化合物の分子内転移反応は例が無いユニークな反応である。

  • 配向性脱離基による反応場制御を鍵とする脱芳香族的官能基化反応の開発

    日本学術振興会  科学研究費助成事業

    研究期間:

    2017年04月
    -
    2019年03月
     

    武藤 慶, 小松田 雅晃, 茅嶋 悠樹, 柳本 愛華, 山口 潤一郎

     概要を見る

    パラジウム触媒を用いてベンジルホスファートやカーボナートに対して、アリルボラートを反応させることで目的とする脱芳香族的アリル化が進行することを見出した。 本反応は触媒的に、かつ一当量のベンジルホスファート類を用いることで進行する。ベンジル位の結合切断を促進する高い電子供与性の配位子をもつパラジウム触媒の適用が重要であり、金属上の電子密度を高くしていくにつれて反応の収率が向上した。生成する化合物の誘導化にも成功し、有用な脂環式ビルディングブロックを簡便に合成できた。さらに、本研究を基盤とし、ベンジル位炭素ー酸素結合切断に加え、他の炭素ーヘテロ結合切断をともなう脱芳香族的官能基化も見いだした。

  • 結合切断反応が拓く革新的分子合成技術の開発

    日本学術振興会  科学研究費助成事業

    研究期間:

    2016年04月
    -
    2019年03月
     

    山口 潤一郎

     概要を見る

    本研究は炭素-炭素結合切断反応を起点とする、触媒的カップリング反応・付加反応に関する革新的な有機合成反応およびそれを促進する新規触媒の開発を目的とした。具体的には芳香族エステルの脱カルボニル型カップリング反応の拡張とシクロプロパンのsp3炭素-炭素結合に対する原子付加反応の開発に着手した。その結果、10種類以上の異なる求核剤を用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を見いだすことができた。また、シクロプロパンに対するヒドロシリル化反応およびヒドロホウ素化反応を開発することに成功した。

  • 多様な複雑チオペプチド抗生物質の高効率合成

    日本学術振興会  科学研究費助成事業

    研究期間:

    2016年04月
    -
    2018年03月
     

    山口 潤一郎

     概要を見る

    本研究では、中分子化合物である複雑チオペプチド抗生物質の多様性合成を目指し、新規カップリング反応/環変換反応によるトリアリールピリジンの迅速合成と、2つの化学ライゲーション法を駆使したペプチド結合形成法を確立する。また、核となるマルチアリールヘテロ環の合成法を確立することを目的とした。
    本年度は、多種類のアリール基で置換されたナフタレン、アントラセンおよび、機能性分子の重要骨格であるベンゾヘテロール化合物の合成に着手した。
    1. 多種類のアリール基で置換されたナフタレン、アントラセンの自在合成:テトラアリールチオフェンオキシドとアラインとの [4+2]付加環化反応を用いることでオクタアリールナフタレン、オクタアリールアントラセン、デカアリールアントラセンを合成した。本手法に従えば、チオフェンに導入するアリール基の種類を変えることで、ナフタレン、アントラセンの望みの位置にアリール基が導入可能となる。
    2. ヘプタアリールインドールの新規合成法の開発:多数の置換基を導入する多置換インドール合成に関しては未だ効率的な手法は限られ、特に3つ以上の異なる官能基を効率的に導入する手法は限られている。他のベンゾヘテロールの合成法に関しても同様の合成上の問題を抱えている。これらが多置換ベンゾヘテロール化学の化学的・物理学的性質・応用への進展を妨げているといっても過言ではない。今回、4つの簡便な部品(ジアリールインドール・アリールボロン酸・アリールブロモアセチレン・アリールアジリジン)を繋げイナミド中間体とした後に、逆電子要請型分子内[4+2]付加環化反応、続く酸化反応によるペンタアリールインドール(PAI)の合成、続く2度のアリール化反応によってヘプタアリールインドール(HAI: heptaarylindole)を合成することに成功した。

  • 芳香族カルボン酸誘導体をカップリング剤とした高難度変換反応の開発

    日本学術振興会  科学研究費助成事業

    研究期間:

    2016年04月
    -
    2018年03月
     

    山口 潤一郎

     概要を見る

    本研究では、先に見出していた2種類の芳香族エステルのカップリング反応(ニッケル触媒による脱エステル型C-Hアリール化反応・ニッケル触媒による鈴木ー宮浦型カップリング反応)を基盤とし、潜在的な求核剤を様々なヘテロ原子を含む化合物や炭素骨格へと大幅に拡大を試みた。すなわち、芳香族エステルから直接炭素―炭素結合形成、炭素―ヘテロ原子結合反応の開発を行った。昨年度は3つの新しい求核剤を見いだしたが、、今年度さらに3つの求核剤を用いた新規芳香族エステルの脱カップリング反応の開発に成功した
    1. ヘテロ芳香環エステルとケトンのα-アリール化反応
    2 芳香族エステルの脱カルボニル型炭素-;リン結合形成反応.
    3. ニッケル触媒による芳香族エステルの脱カルボニル型アルキル化反応
    1:用いるヘテロ芳香族エステルには、基質制限があるものの、ヘテロ芳香族エステルとケトンからクライゼン縮合が進行することなく、α-アリールケトンが得られる。独自に開発したdcypt[3,4-ビス(ジシクロヘキシルホスフィノ)チオフェン]が最も効果的である。2:広範な芳香族フェニルエステルで反応が進行し、リン求核剤としてはジアリールホスフィンオキシドやジアルキル亜リン酸が適用できる。3: 興味深いことにジアルキル塩化アルミが最も効率的なアルキル化剤として働く。本反応は、芳香族フェニルエステルに加えて、芳香族アルキルエステルに対しても適用可能である。
    このように自身で開発した芳香族エステルのカップリング反応の可能性を大幅に拡張することに成功した。

  • 環拡大反応を利用したフシコクシンAの全合成研究

    日本学術振興会  科学研究費助成事業

    研究期間:

    2016年04月
    -
    2018年03月
     

    山口 潤一郎

     概要を見る

    天然物Fusicoccin A の全合成と各種誘導体合成および生物活性評価による構造活性相関研究を目指し、三環式炭素骨格の合成に挑戦した。ベンゼンに4炭素ユニットの側鎖を導入し、4-6-4炭素骨格を5-8-5縮環構造に変換するという極めて斬新な合成計画であった。すなわち、置換ベンゼンから連続的な環拡大反応で行い 、6員環を8員環に変換する。市販化合物から7工程で得られた置換ベンゼンに、Rh(II)触媒を作用させてBuchner反応を試みた。その結果、立体選択的なシクロプロパン化条件を見出し、続く中間体のジビニルシクロプロパン転位により、7員環をほぼ単一の生成物で定量的に得た。

  • 革新的直接カップリング反応を促進する二官能性触媒の創製

    日本学術振興会  科学研究費助成事業

    研究期間:

    2013年04月
    -
    2016年03月
     

    山口 潤一郎

     概要を見る

    本研究では、分子結合活性化による直接的カップリング反応の新しい分子触媒を開発することを目的として研究を行った。合成した触媒を用いて、これまで達成できなかった、炭素-水素(結合、炭素-酸素結合、炭素-炭素結合を同時に活性化できる次世代カップリング法を開発した。直接的不斉カップリングも視野にいれ本手法を活用する事で生物活性物質の合成に応用することができた。

  • 多分子結合活性化による生物活性分子の合成研究

    日本学術振興会  科学研究費助成事業

    研究期間:

    2013年04月
    -
    2015年03月
     

    山口 潤一郎

     概要を見る

    本研究では、不活性C-H結合、C-O結合およびC-C結合を活性化・官能基化できる新触媒・新反応を開発し、生物活性分子の超短工程合成を実現する。主に医薬品や天然物等の生物活性化合物に標的を設定し、反応開発研究と合成研究が連動するダイナミックな研究を行う。生物活性分子の迅速合成の為に必須である、具体的にはヘテロ芳香環、オレフィン、sp3炭素を含む最も理想的なC-H結合活性化、安定で豊富に存在するC-O結合活性化、さらにユビキタス官能基であるエステルのC-C結合活性化反応を合成化学的に実用的な反応に飛躍的に発展させる。今年度は、エステルのC-C結合活性化反応に注力し、ニッケル触媒を用いた有機ボロン酸との新規カップリング反応、脱エステル型カップリング反応を駆使した、トリチアゾリルペプチド抗生物質の合成に成功した。また、C-H結合及びC-O結合の活性化によりカルボニル化合物のα-アリール化反応や、イミダゾール類の触媒的直接的アリール化反応も見出した。

  • 炭素ー水素結合活性化に基づく生物活性物質の合成

    日本学術振興会  科学研究費助成事業

    研究期間:

    2011年04月
    -
    2013年03月
     

    山口 潤一郎

     概要を見る

    本研究では、不活性C-H結合を活性化・官能基化する新触媒・新反応を開発し、生物活性物質の超短工程合成を実現することを目的とした。昨年度に引き続き研究を行なった結果、ヘテロビアリール骨格を有する生物活性分子の合成を加速する新規芳香環直接アリール化反応を開発することができた。
    1. Ni触媒を用いた脱エステル型カップリング反応 既にアリール化剤としてハロゲン化アリール、フェノール誘導体をもちいたNi触媒によるアゾール類の直接アリール化反応を見出していたが、今回芳香族エステルをアリール化剤とした新たなカップリング反応を発見した。本反応を応用したmuscoride Aの形式全合成も達成した
    2.嵩高いビアリール合成を促進する新規パラジウム触媒の開発 独自に開発したパラジウム触媒によるチオフェン類とアリールボロン酸とのC4位選択的なC-Hアリール化反応を基盤として、嵩高いヘテロビアリール骨格の構築を様々な配位子を用いて検討を行なった。その結果、ビスオキサゾリン配位子を用いた場合、劇的な反応加速効果がみられ、嵩高いアリールボロン酸においても良好な収率でチオフェンやフラン、インドールなどのヘテロ芳香環と反応が進行することを見出した。さらにキラル配位子を用いた不斉反応へと展開し、不斉C-Hビアリールカップリング反応の開発にも成功した
    3. C-Hアリール化のメディシナルケミストリーへの応用 σ1受容体として有効な化合物を探索した結果、スピロ環を有するアリールチオフェン骨格がσ1受容体として優れていることが明らかとなっている。今回、独自で開発したC5位およびC4位選択的チオフェンのアリール化反応を用いた、最終段階での直接C-Hアリール化反応を駆使する事でより幅広く誘導体を合成することに成功した

  • 天然物合成を指向したインドールとアジンのC. H直接連結反応の開発

    日本学術振興会  科学研究費助成事業

    研究期間:

    2010年
    -
    2011年
     

    山口 潤一郎

     概要を見る

    生物活性天然物や医農薬化合物に頻繁に見られるインドールーアジン骨格を最も理想的かつ直接的に構築する新規反応を開発した。開発した反応を駆使することでdragmacidin D, eudistomin Uなどの天然物有機化合物群合成への応用展開に成功した。

  • 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

    研究期間:

    2008年
     
     
     

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

    研究期間:

    2008年
     
     
     

▼全件表示

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 ( 17 ) 2393 - 2396  2018年09月

     概要を見る

    © 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年07月

     概要を見る

    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 ( 7 ) 1358 - 1361  2018年07月

     概要を見る

    © 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年05月

     概要を見る

    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年02月

     概要を見る

    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, Toshiyuki Sakai, Kenichiro Itami, Kenichiro Itami, Junichiro Yamaguchi, Junichiro Yamaguchi, Takayoshi Suzuki, Takayoshi Suzuki

    Bioorganic and Medicinal Chemistry   26 ( 3 ) 775 - 785  2018年02月

     概要を見る

    © 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年

     概要を見る

    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年01月

     概要を見る

    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年

    書評論文,書評,文献紹介等  

     概要を見る

    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年

     概要を見る

    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年

     概要を見る

    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年01月

     概要を見る

    © 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 α-Arylation of Ketones with Heteroaromatic Esters

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

    Synlett   28 ( 19 ) 2599 - 2603  2017年12月

     概要を見る

    © Georg Thieme Verlag Stuttgart, New York. Heteroaromatic esters were found to be applicable as an arylating agent for the Pd-catalyzed α-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 α-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年11月

     概要を見る

    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年10月

    書評論文,書評,文献紹介等  

     概要を見る

    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 σ<inf>1</inf>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, Erik Laurini, Maurizio Fermeglia, Maurizio Fermeglia, Sabrina Pricl, Sabrina Pricl, Bernhard Wünsch, Bernhard Wünsch

    ChemMedChem   12 ( 13 ) 1070 - 1080  2017年07月

     概要を見る

    © 2017 Wiley-VCH Verlag GmbH &amp; Co. KGaA, Weinheim Spirocyclic thiophene derivatives represent promising σ1ligands with high σ1affinity and selectivity over the σ2subtype. 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 9 a–c resulted in a set of 53 compounds with high diversity. This set of compounds was analyzed with respect to σ1affinity, σ1/σ2selectivity, lipophilicity (logD7.4), lipophilicity-corrected ligand efficiency (LELP), and molecular target interactions. The most promising candidates were pyridyl-substituted thiazole derivatives 33 c (2-(1-benzyl-4-ethoxypiperidin-4-yl)-5-(pyridin-3-yl)thiazole) and 34 c (2-(1-benzyl-4-ethoxypiperidin-4-yl)-5-(pyridin-4-yl)thiazole), possessing low-nanomolar σ1affinity (Ki=1.3 and 1.9 nm), high σ1/σ2selectivity (&gt;1500-fold), low lipophilicity (logD7.4=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 33 c and 34 c, 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年06月

     概要を見る

    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年05月

     概要を見る

    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年05月

     概要を見る

    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年04月

    書評論文,書評,文献紹介等  

     概要を見る

    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年03月

     概要を見る

    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年03月

     概要を見る

    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年02月

     概要を見る

    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年02月

    書評論文,書評,文献紹介等  

     概要を見る

    © 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年10月

     概要を見る

    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年09月

     概要を見る

    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, Kenichiro Itami

    Topics in Current Chemistry   374 ( 4 )  2016年08月

    書評論文,書評,文献紹介等  

     概要を見る

    © 2016, Springer International Publishing Switzerland. 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年08月

    書評論文,書評,文献紹介等  

     概要を見る

    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年04月   [ 国際誌 ]

     概要を見る

    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年03月

     概要を見る

    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年01月

     概要を見る

    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年

     概要を見る

    © 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 σ<inf>1</inf>receptor affinity

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

    MedChemComm   7 ( 2 ) 327 - 331  2016年

     概要を見る

    © The Royal Society of Chemistry 2016. New thiazole analogues 2 of spirocyclic thiophenes 1, which are known to show high σ1receptor affinities, have been developed as potentially better σ1receptor 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 σ1affinity. The same σ1affinity of the regioisomeric thiazoles 2b and 2c can be explained by fast rotation around the piperidine-thiazole 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年06月

     概要を見る

    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年06月

     概要を見る

    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年03月

     概要を見る

    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年

     概要を見る

    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年

     概要を見る

    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年01月

     概要を見る

    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 α-arylation of esters and amides with phenol derivatives

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

    Chemical Communications   51 ( 5 ) 855 - 857  2015年

     概要を見る

    © The Royal Society of Chemistry. A nickel-catalyzed α-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(dicyclohexylphosphino)thiophene (dcypt), and K3PO4, various esters and amides undergo α-arylation with O-arylpivalates or O-arylcarbamates to afford the corresponding coupling products. The thus obtained α-aryl esters and amides are useful precursors of privileged motifs such as α-arylcarboxylic acids and β-arylamines. This journal is

    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年01月

     概要を見る

    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年10月

     概要を見る

    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

  • β-selective C-H arylation of pyrroles leading to concise syntheses of lamellarins C and I

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

    Journal of the American Chemical Society   136 ( 38 ) 13226 - 13232  2014年09月

     概要を見る

    © 2014 American Chemical Society. The first general β-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 β-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年08月

     概要を見る

    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年08月

    研究発表ペーパー・要旨(国際会議)  

  • 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年06月

     概要を見る

    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 α-arylation of ketones with phenol derivatives

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

    Angewandte Chemie - International Edition   53 ( 26 ) 6791 - 6794  2014年06月

     概要を見る

    The nickel-catalyzed α-arylation of ketones with readily available phenol derivatives (esters and carbamates) provides access to useful α-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. The nickel-catalyzed α-arylation of ketones with readily available phenol derivatives (esters and carbamates) provides access to useful α-arylketones. The use of 3,4-bis(dicyclohexylphosphino)thiophene (dcypt) as an air-stable ligand enables this transformation. The intermediate of an assumed C-O oxidative addition was isolated and characterized by X-ray crystal-structure analysis. © 2014 WILEY-VCH Verlag GmbH &amp; Co. KGaA, Weinheim.

    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年05月

     概要を見る

    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年

     概要を見る

    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年01月

     概要を見る

    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年

     概要を見る

    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年11月

    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年11月

     概要を見る

    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年11月

    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年09月

     概要を見る

    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年06月

     概要を見る

    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年04月

    CiNii

  • Improvement of σ<inf>1</inf>receptor affinity by late-stage C-H-bond arylation of spirocyclic lactones

    Christina Meyer, Benedikt Neue, Dirk Schepmann, Shuichi Yanagisawa, Junichiro Yamaguchi, Ernst Ulrich Würthwein, Kenichiro Itami, Bernhard Wünsch

    Bioorganic and Medicinal Chemistry   21 ( 7 ) 1844 - 1856  2013年04月

     概要を見る

    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 α-arylation of the thiophene moiety was performed with the catalytic system PdCl2/2,2′-bipyridyl/Ag2CO3, whereas the β-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 α-positions providing 4′-mono-, 6′-mono- and 4′,6′-diarylated thiophenes 22-26a-c. Compounds with an additional aryl moiety at the &#039;upper left (top)&#039; position (1′-position of 13, 3′-position of 14, 4′-position of 18) showed increased σ1affinity compared to the non-arylated parent compounds. A phenyl moiety at the &#039;left&#039; position (2′-position in 20a) also increased the σ1affinity but to a lower extent. A considerable reduction of σ1affinity 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 σ1receptor. 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. © 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   2013 ( 1 ) 19 - 30  2013年01月

    書評論文,書評,文献紹介等  

     概要を見る

    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年

     概要を見る

    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年

     概要を見る

    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

  • 炭素-水素結合直接変換を鍵とする生物活性物質の合成 (特集 C-H結合の活性化研究)

    山口 潤一郎, 伊丹 健一郎

    ファインケミカル : 調査・資料・報道・抄録   41 ( 10 ) 38 - 45  2012年10月

    CiNii

  • Late-stage C-H bond arylation of spirocyclic σ 1 ligands for analysis of complementary σ 1 receptor surface

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

    European Journal of Organic Chemistry   ( 30 ) 5972 - 5979  2012年10月

     概要を見る

    Direct C-H bond arylation in the α- and β-positions of spirocyclic thiophenes containing various functional groups (amine, ether, acetal, lactone) was accomplished. Selective phenylation in the α-position of the thiophene ring was achieved by using the catalytic system PdCl 2/bipy/Ag 2CO 3. The introduction of phenyl moieties to the β-position was performed with the catalytic system PdCl 2/P[OCH(CF 3) 2] 3/Ag 2CO 3. 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 Ï 1 affinities (e.g., 4a: K i = 1.6 nM; 5a: K i = 2.4 nM), indicating an additional hydrophobic pocket on the complementary Ï 1 receptor protein. A phenyl moiety in position C (at the bottom position) is not tolerated by the Ï 1 receptor (e.g., 12: K i = 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. Diverse spirocyclic thiophenes were synthesized regioselectively by direct C-H bond arylation using the catalytic systems PdCl 2/bipy/Ag 2CO 3 and PdCl 2/ P[OCH(CF 3) 2] 3/Ag 2CO 3. Compounds bearing the phenyl moiety at the top position and the sulfur atom in left position show the highest Ï 1 affinity. © 2012 2012 Wiley-VCH Verlag GmbH &amp; Co. KGaA, Weinheim.

    DOI

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

    Keika Hattori, Kazuya Yamaguchi, Junichiro Yamaguchi, Kenichiro Itami

    TETRAHEDRON   68 ( 37 ) 7605 - 7612  2012年09月

     概要を見る

    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 σ<inf>1</inf>ligands: Generation of a pharmacophore model and analysis of the reverse binding mode by Docking into a 3D homology model of the σ<inf>1</inf>receptor

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

    Journal of Medicinal Chemistry   55 ( 18 ) 8047 - 8065  2012年09月

     概要を見る

    To explore the hydrophobic binding region of the σ1receptor protein, regioisomeric spirocyclic thiophenes 9-11 were developed as versatile building blocks. Regioselective α- and β-arylation using the catalyst systems PdCl2/bipy/Ag2CO3and PdCl2/P[OCH(CF3)2]3/Ag2CO3allowed the introduction of various aryl moieties at different positions in the last step of the synthesis. The increasing σ1affinity 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 σ1affinity. The main features of the pharmacophore model developed for this class of σ1ligands are a positive ionizable group, a H-bond acceptor group, two hydrophobic moieties, and one hydrophobic aromatic group. Docking of the ligands into a σ13D 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 &quot;top&quot; (compounds 2, 3, 7, and 8) and &quot;left&quot; (compounds 4, 5, and 6) positions, respectively. © 2012 American Chemical Society.

    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年08月

     概要を見る

    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年01月

     概要を見る

    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年

     概要を見る

    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年

    書評論文,書評,文献紹介等  

     概要を見る

    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年09月

     概要を見る

    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

  • 炭素-水素結合直接変換を鍵とする生物活性物質の合成

    山口 潤一郎, 伊丹 健一郎

    觸媒 = Catalyst   53 ( 5 ) 293 - 297  2011年08月

    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年06月

     概要を見る

    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 σ <inf>1</inf> 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 Würthwein, Kenichiro Itami, Bernhard Wünsch

    Organic and Biomolecular Chemistry   9 ( 23 ) 8016 - 8029  2011年

     概要を見る

    The hypothesis that the σ 1 receptor will tolerate an additional aryl moiety in position 1 of the spirocyclic system was based on spirocyclic pyrazole derivatives, pharmacophore models of σ 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 σ 1 receptor protein. The catalyst system PdCl 2/2,2′-bipyridyl/Ag 2CO 3 is able to introduce various aryl groups onto the α-positions of spirocyclic thiophene derivatives 5 and 6 to afford the target aryl-appended spirocyclic thiophenes 3 and 4. Although the σ 1 affinity of the 1-phenyl substituted spirocyclic thiophenes 3a and 4a is slightly reduced compared with the σ 1 affinity of the non-arylated compounds 5 and 6, both compounds represent very potent σ 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 σ 1 receptor protein. The substitution pattern of the additional phenyl moiety has only weak effects on the σ 1 affinity. Even ligands 3f and 4h with extended naphthyl residue show high σ 1 affinity. However, decrease of σ 1 affinity by extension of the π-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 σ 1 receptor. © The Royal Society of Chemistry 2011.

    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年

    書評論文,書評,文献紹介等  

     概要を見る

    (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年04月

     概要を見る

    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年02月

     概要を見る

    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年

    DOI PubMed

  • Direct asymmetric α-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年

     概要を見る

    trans-tert-Butyldimethylsiloxy-l-proline displays greater catalytic activity and affords higher enantioselectivity than the parent proline in the a-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), α-amino carbonyl derivatives, which are important synthetic intermediates, are obtained in good yield and with excellent enantioselectivity. © 2008 Wiley-VCH Verlag GmbH&amp;Co. KGaA.

    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年

     概要を見る

    (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 α-aminoxylation of aldehydes and ketones

    Yujiro Hayashi, Junichiro Yamaguchi, Tatsunobu Sumiya, Kazuhiro Hibino, Mitsuru Shoji

    Journal of Organic Chemistry   69 ( 18 ) 5966 - 5973  2004年09月

    書評論文,書評,文献紹介等  

     概要を見る

    The direct proline-catalyzed asymmetric α-aminoxylation of aldehydes and ketones has been developed using nitrosobenzene as an oxygen source, affording α-anilinoxy-aldehydes and -ketones with excellent enantioselectivity. Reaction conditions have been optimized, and low temperature (-20 °C) was found to be a key for the successful α-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 α-aminoxylation of ketones

    Yujiro Hayashi, Junichiro Yamaguchi, Tatsunobu Sumiya, Mitsuru Shoji

    Angewandte Chemie - International Edition   43 ( 9 ) 1112 - 1115  2004年

     概要を見る

    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 α-aminooxylation of aldehydes

    Yujiro Hayashi, Junichiro Yamaguchi, Kazuhiro Hibino, Mitsuru Shoji

    Tetrahedron Letters   44 ( 45 ) 8293 - 8296  2003年11月

     概要を見る

    The direct catalytic enantioselective α-aminooxylation of aldehydes has been developed using nitrosobenzene as the oxygen source and L-proline as catalyst, affording versatile α-aminooxylated aldehydes in high yield with excellent enantioselectivities. © 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年12月

     概要を見る

    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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他学部・他研究科等兼任情報

  • 理工学術院   大学院先進理工学研究科

学内研究所・附属機関兼任歴

  • 2022年
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    2024年

    理工学術院総合研究所   兼任研究員

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    カーボンニュートラル社会研究教育センター   兼任センター員

特定課題制度(学内資金)

  • 芳香族ケトンの脱アシル型/脱酸素型カップリング反応の開発

    2022年  

     概要を見る

    我々は、ニッケルもしくはパラジウム触媒を用いた芳香族ケトンの脱アシル型カップリング反応を開発した。塩基存在下、芳香族ケトン(Ar1–COR)と芳香族エステル(Ar2–CO2R)を反応させるとクライゼン縮合とレトロクライゼン縮合が進行し、芳香族エステル(Ar1–CO2R)が得られることを見いだした。この反応と芳香族エステルの種々の脱カルボニル型変換反応を同一容器内で行うことで、形式的な脱アシル型カップリング反応を可能とした。

  • 新奇カルベン配位子の開発と不活性結合の含フッ素官能基化反応

    2022年  

     概要を見る

    本研究では、超高電子供与性かつ嵩高い新奇N-ヘテロ環状カルベン(NHC)配位子をもつ金属触媒を開発する。開発した触媒を用いて、最高難度クロスカップリングである不活性結合のトリフルオロメチル化(CF3化)を目指す。具体的には、不活性結合に主に芳香環(Ar)C–NO2結合を選定、配位子はアブノーマルNHCであるイソインドリニリデン(IDy)とイソキノリニリデン(IQy)を合成を試みた。現状ではアブノーマル配位子の合成は達成できていないが、前駆体の合成に成功した。今後はここから金属触媒との錯体化の条件検討を行う予定である。ニトロ基の活性化に関しては、Pd/BrettPhos触媒存在下、アミノアセトニトリルをシアノ化剤に用いると、ニトロアレーンの脱ニトロ型シアノ化反応が進行することを見いだした。本反応は、金属シアノ化剤やハロアレーンを用いない新たなシアノ化反応である。興味深いことに、金属シアノ化剤を用いると目的の芳香族ニトリルの収率が低下した。本反応はヘテロ芳香環や医薬品誘導体などを含む、種々のニトロアレーンでシアノ化が進行した。また、本反応を用いた逐次的カップリングによる三成分連結にも成功した。

  • 芳香族エステルの脱酸素型変換反応の開発

    2021年  

     概要を見る

    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年  

     概要を見る

    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年  

     概要を見る

    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年  

     概要を見る

    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年  

     概要を見る

    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年  

     概要を見る

    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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