Updated on 2024/03/05

写真a

 
SAKAKURA Akira
 
Organization
Faculty of Environmental, Life, Natural Science and Technology Professor
Position
Professor
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Degree

  • 学術 ( 2000.10   名古屋大学 )

Research Interests

  • 生物有機化学

  • 有機合成化学

Research Areas

  • Nanotechnology/Materials / Chemistry and chemical methodology of biomolecules

  • Nanotechnology/Materials / Synthetic organic chemistry

Education

  • Nagoya University   大学院人間情報学研究科  

    1995.4 - 2000.6

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    Country: Japan

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  • Nagoya University   大学院理学研究科   化学専攻

    1993.4 - 1995.3

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    Country: Japan

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  • Nagoya University   理学部   化学科

    1989.4 - 1993.3

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    Country: Japan

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Research History

  • Okayama University   Graduate School of Natural Science and Technology   Professor

    2012.9

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  • Nagoya University   EcoTopia Science Institute   Associate Professor

    2007.4 - 2012.8

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  • Nagoya University   Graduate School of Engineering   Associate Professor

    2003.3 - 2007.3

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  • University of Tsukuba   Department of Chemistry   Assistant Professor

    2001.4 - 2003.2

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Professional Memberships

Committee Memberships

  • 日本化学会中国四国支部   岡山地区幹事  

    2015.4 - 2017.3   

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    Committee type:Academic society

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  • 有機合成化学協会中国四国支部   事務局  

    2013.4   

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  • 日本化学会東海支部   代表正会員  

    2011.4 - 2013.3   

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    Committee type:Academic society

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Papers

  • Visible-Light-Photoexcited Palladium-Catalyzed Silylmethylation of Benzyl Alcohol Derivatives Invited Reviewed

    Haruki Mizoguchi, Akira Sakakura, Ryuji Yoshida, Haruka Ikeda

    Synlett   34 ( 20 )   2451 - 2454   2023.7

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

    DOI: 10.1055/s-0042-1752736

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  • Enantioselective construction of beta-hydroxy-alpha,alpha-disubstituted alpha-amino acid derivatives via direct aldol reaction of alpha-imino esters Reviewed

    Yuya Araki, Masato Hanada, Yoshiko Iguchi, Haruki Mizoguchi, Akira Sakakura

    TETRAHEDRON   110   2022.3

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    Authorship:Last author, Corresponding author   Language:English   Publishing type:Research paper (scientific journal)   Publisher:PERGAMON-ELSEVIER SCIENCE LTD  

    The beta-hydroxy-alpha,alpha-disubstituted alpha-amino acid is a valuable structural motif for research in the field of bioorganic chemistry and in the development of peptide drugs. This report describes the enantioselective direct-aldol reaction of alpha-imino esters with glyoxylate esters. We discovered that a catalytic amount of Co(OAc)(2)-pybox complex catalyzed the aldol reaction of salicylaldehyde-derived alpha-imino esters with benzyl glyoxylate in good yield and enantioselectivity. In addition, hydrolysis of the imine moiety of the aldol products followed by Boc protection of the resultant amino group gave the N-Boc-protected amino acid derivatives. (C) 2022 Elsevier Ltd. All rights reserved.

    DOI: 10.1016/j.tet.2022.132695

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  • Annulative coupling of vinylboronic esters: aryne-triggered 1,2-metallate rearrangement Reviewed

    Haruki Mizoguchi, Hidetoshi Kamada, Kazuki Morimoto, Ryuji Yoshida, Akira Sakakura

    Chemical Science   13 ( 33 )   9580 - 9585   2022

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

    A stereoselective annulative coupling of a vinylboronic ester ate-complex with arynes producing cyclic borinic esters has been developed. An annulation reaction that proceeded through the formation of two C-C bonds and a C-B bond was realized by exploiting a 1,2-metallate rearrangement of boronate triggered by the addition of a vinyl group to the strained triple bond of an aryne. The generated aryl anion would then cyclize to a boron atom to complete the annulation cascade. The annulated borinic ester could be converted to boronic acids and their derivatives by oxidation, halogenation, and cross-coupling. Particularly, halogenation and Suzuki-Miyaura coupling proceeded in a site-selective fashion and produced highly substituted alkylboronic acid derivatives.

    DOI: 10.1039/D2SC02623F

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  • Toward the Synthesis of Paspaline-Type Indole-Terpenes: Stereoselective Construction of Core Scaffold with Contiguous Asymmetric Quaternary Carbon Centers Reviewed

    Ichiro Hayakawa, Naochika Matsumaru, Akira Sakakura

    The Journal of Organic Chemistry   86 ( 14 )   9802 - 9810   2021.7

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

    DOI: 10.1021/acs.joc.1c01193

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  • Strain-release Difunctionalization of C–C σ- and π-bonds of an Organoboron Ate-complex through 1,2-Metallate Rearrangement Invited Reviewed

    Haruki Mizoguchi, Akira Sakakura

    Chemistry Letters   50 ( 4 )   792 - 799   2021.4

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

    DOI: 10.1246/cl.200926

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  • Reusable Silica‐Supported Ammonium BINSate Catalysts for Enantio‐ and Diastereoselective Friedel–Crafts‐Type Double Aminoalkylation of N ‐Alkylpyrroles with Aldimines

    Manabu Hatano, Xue Zhao, Takuya Mochizuki, Kyogo Maeda, Ken Motokura, Kazuaki Ishihara

    Asian Journal of Organic Chemistry   10 ( 2 )   360 - 365   2021.2

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    Publishing type:Research paper (scientific journal)   Publisher:Wiley  

    DOI: 10.1002/ajoc.202000603

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  • Dual Inhibition of γ-Tubulin and Plk1 Induces Mitotic Cell Death Reviewed

    Haruna Ebisu, Kana Shintani, Takumi Chinen, Yoko Nagumo, Shuya Shioda, Taisei Hatanaka, Akira Sakakura, Ichiro Hayakawa, Hideo Kigoshi, Takeo Usui

    Frontiers in Pharmacology   11   2021.1

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    Publishing type:Research paper (scientific journal)   Publisher:Frontiers Media SA  

    α/β-Tubulin inhibitors that alter microtubule (MT) dynamics are commonly used in cancer therapy, however, these inhibitors also cause severe side effects such as peripheral neuropathy. γ-Tubulin is a possible target as antitumor drugs with low side effects, but the antitumor effect of γ-tubulin inhibitors has not been reported yet. In this study, we verified the antitumor activity of gatastatin, a γ-tubulin specific inhibitor. The cytotoxicity of gatastatin was relatively weak compared with that of the conventional MT inhibitors, paclitaxel and vinblastine. To improve the cytotoxicity, we screened the chemicals that improve the effects of gatastatin and found that BI 2536, a Plk1 inhibitor, greatly increases the cytotoxicity of gatastatin. Co-treatment with gatastatin and BI 2536 arrested cell cycle progression at mitosis with abnormal spindles. Moreover, mitotic cell death induced by the combined treatment was suppressed by the Mps1 inhibitor, reversine. These findings suggest that co-treatment with Plk1 and γ-tubulin inhibitors causes spindle assembly checkpoint-dependent mitotic cell death by impairing centrosome functions. These results raise the possibility of Plk1 and γ-tubulin inhibitor co-treatment as a novel cancer chemotherapy.

    DOI: 10.3389/fphar.2020.620185

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  • Kinetic Resolution of α-Nitrolactones by Catalytic Asymmetric Hydrolysis or Ester–Amide Exchange Reaction Reviewed

    Akira Sakakura, Ryota Nakao, Yudai Fujii, Ichiro Hayakawa, Haruki Mizoguchi

    Synlett   31 ( 20 )   2018 - 2022   2020.12

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    Authorship:Last author, Corresponding author   Language:English   Publishing type:Research paper (scientific journal)   Publisher:Georg Thieme Verlag {KG}  

    <title>Abstract</title>
    C
    1-Symmetric chiral ammonium salt catalysts induced a kinetic resolution of racemic α-nitrolactones through an asymmetric ester–amide exchange reaction. The corresponding amides were obtained with high enantioselectivities and high S (= k
    fast/k
    slow) values. This reaction system is a useful approach for obtaining carbocyclic quaternary α-nitroamides as chiral building blocks.

    DOI: 10.1055/s-0040-1707303

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  • Enantioselective Diels–Alder Reaction of 3-Nitrocoumarins Promoted by Chiral Organoammonium Salt Catalysts Reviewed

    Akira Sakakura, Yudai Fujii, Ryota Nakao, Saki Sugihara, Keita Fujita, Yuya Araki, Takayuki Kudoh, Ichiro Hayakawa, Haruki Mizoguchi

    Synlett   31 ( 20 )   2013 - 2017   2020.12

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    Authorship:Last author, Corresponding author   Language:English   Publishing type:Research paper (scientific journal)   Publisher:Georg Thieme Verlag {KG}  

    <title>Abstract</title>An enantioselective Diels–Alder reaction of 3-nitrocoumarins has been developed. A tryptophan-derived C
    1-symmetric organoammonium thiourea catalyst promoted the reaction of 3-nitrocoumarins with Danishefsky’s diene to give the corresponding adducts with good enantioselectivity (up to 94% ee). One of the resulting adducts was converted into a chiral carbocyclic quaternary β-amino alcohol.

    DOI: 10.1055/s-0040-1707302

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  • Structure Optimization of Gatastatin for the Development of gamma-Tubulin-Specific Inhibitor Reviewed

    Kana Shintani, Haruna Ebisu, Minagi Mukaiyama, Taisei Hatanaka, Takumi Chinen, Daisuke Takao, Yoko Nagumo, Akira Sakakura, Ichiro Hayakawa, Takeo Usui

    ACS MEDICINAL CHEMISTRY LETTERS   11 ( 6 )   1125 - 1129   2020.6

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

    Gatastatin (O-7-benzyl glaziovianin A) is a gamma-tubulin-specific inhibitor that is used to investigate gamma-tubulin function in cells. We have previously reported that the unsubstituted phenyl ring of the O-7-benzyl group in gatastatin is important for gamma-tubulin inhibition. To obtain further structural information regarding gamma-tubulin inhibition, we synthesized several gatastatin derivatives containing a fixed O-7-benzyl moiety. Modifications of the B-ring resulted in drastic decrease in cytotoxicity, abnormal spindle formation activity, and inhibition of microtubule (MT) nucleation. In contrast, various O-6-alkylated gatastatin derivatives showed potent cytotoxicity, induced abnormal spindle formation, and inhibited MT nucleation. We had previously reported that O-6-benzyl glaziovianin A is a potent alpha/beta-tubulin inhibitor; thus, these new results suggest that the O-6-position restricts affinity for alpha/beta- and gamma-tubulin. Considering that an O-7-benzyl group increases specificity for gamma-tubulin, more potent and specific gamma-tubulin inhibitors can be generated through O-6-modifications of gatastatin.

    DOI: 10.1021/acsmedchemlett.9b00526

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  • Formal Total Synthesis of Manzacidin B via Sequential Diastereodivergent Henry Reaction Reviewed

    Yuya Araki, Natsumi Miyoshi, Kazuki Morimoto, Takayuki Kudoh, Haruki Mizoguchi, Akira Sakakura

    JOURNAL OF ORGANIC CHEMISTRY   85 ( 2 )   798 - 805   2020.1

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    A formal total synthesis of manzacidin B is described. beta,beta-Disubstituted gamma-hydroxy-beta-aminoalcohol, the key structure of manzacidin B, is stereoselectively constructed via sequential Henry reactions. By taking advantage of noncovalent interactions, such as intramolecular hydrogen bonding and chelation, we could diastereodivergently control the stereoselectivity of the Henry reaction.

    DOI: 10.1021/acs.joc.9b02811

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  • Synthesis of functionalized cyclopropylboronic esters based on a 1,2-metallate rearrangement of cyclopropenylboronate Reviewed

    Haruki Mizoguchi, Masaya Seriu, Akira Sakakura

    Chemical Communications   56 ( 99 )   15545 - 15548   2020

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    <p>A procedure converting tribromocyclopropane to densely functionalized β-selenocyclopropylboronic ester using the 1,2-metallate rearrangement of a boron ate-complex has been developed.</p>

    DOI: 10.1039/d0cc07134j

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  • Toward the Synthesis of SB-203207: Construction of Four Contiguous Nitrogen-Containing Stereogenic Centers Reviewed

    Ichiro Hayakawa, Anna Nagayasu, Akira Sakakura

    The Journal of Organic Chemistry   84 ( 23 )   15614 - 15623   2019.12

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

    DOI: 10.1021/acs.joc.9b02627

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  • Enantioselective 1,3-Dipolar Cycloaddition Reaction of Nitrones with α-(Acyloxy)acroleins Catalyzed by Dipeptide-Derived Chiral Tri- or Diammonium Salts Reviewed

    Chihiro Kidou, Haruki Mizoguchi, Tatsuo Nehira, Akira Sakakura

    Synlett   30 ( 15 )   1835 - 1839   2019.9

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    Authorship:Last author, Corresponding author   Language:English   Publishing type:Research paper (scientific journal)   Publisher:Georg Thieme Verlag {KG}  

    Organoammonium salts of dipeptide-derived chiral triamines or diamines with TfOH catalyzed the enantioselective 1,3-dipolar cycloaddition reactions of α-acyloxyacroleins with nitrones to give the corresponding adducts in good yields (up to 96%) and with high diastereo- and enantioselectivities (up to 89% ee). Although α-(p-methoxybenzoyloxy)acrolein is rather unstable under the reaction conditions, α-(3-pyrroline-1-carbonyloxy)acrolein is stable enough to be smoothly converted into the corresponding adducts with the aid of the chiral organoammonium salt catalysts.

    DOI: 10.1055/s-0039-1690133

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  • Toward the Synthesis of Yuzurimine-Type Alkaloids: Stereoselective Construction of the Heterocyclic Portions of Deoxyyuzurimine and Macrodaphnine Reviewed International journal

    Ichiro Hayakawa, Ryosuke Nagatani, Masaki Ikeda, Dong-eun Yoo, Keita Saito, Hideo Kigoshi, Akira Sakakura

    Organic Letters   21 ( 16 )   6337 - 6341   2019.8

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    The heterocyclic portions of yuzurimine-type alkaloids, such as deoxyyuzurimine and macrodaphnine, were synthesized by using a stereoselective hydroboration-oxidation reaction to install the C20 methyl group, the intramolecular Mitsunobu reaction to construct the E-ring portion, and the intramolecular SN2 reaction to construct the F-ring portion as key steps.

    DOI: 10.1021/acs.orglett.9b02232

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  • Thioureas as Highly Active Catalysts for Biomimetic Bromocyclization of Geranyl Derivatives Reviewed

    Miyuki Terazaki, Kei-ichi Shiomoto, Haruki Mizoguchi, Akira Sakakura

    Organic Letters   21 ( 7 )   2073 - 2076   2019.4

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    DOI: 10.1021/acs.orglett.9b00352

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  • Catalytic enantioselective Hosomi–Sakurai reaction of α-ketoesters promoted by chiral copper(ii) complexes Reviewed

    Yutaro Niwa, Mayu Miyake, Ichiro Hayakawa, Akira Sakakura

    Chemical Communications   55 ( 27 )   3923 - 3926   2019

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    <p>The first catalytic enantioselective Hosomi−Sakurai reaction of α-ketoesters.</p>

    DOI: 10.1039/C9CC01159E

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  • Chiral Pyrophosphoric Acid Catalysts for the para-Selective and Enantioselective Aza-Friedel–Crafts Reaction of Phenols Reviewed

    Akira Sakakura, Manabu Hatano, Kazuaki Ishihara, Haruka Okamoto, Kohei Toh, Takuya Mochizuki, Hidefumi Nakatsuji

    Synthesis   50 ( 23 )   4577 - 4590   2018.12

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    Authorship:Corresponding author   Language:English   Publishing type:Research paper (scientific journal)   Publisher:Georg Thieme Verlag {KG}  

    Chiral BINOL-derived pyrophosphoric acid catalysts were developed and used for the regio- and enantioselective aza-Friedel–Crafts reaction of phenols with aldimines. ortho/para-Directing phenols could react at the para-position selectively with moderate to good enantioselectivities. Moreover, the gram-scale transformation of a product into the key intermediate for the antifungal agent (R)-bifonazole was demonstrated.

    DOI: 10.1055/s-0037-1610250

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  • Enantioselective aza-Friedel–Crafts reaction of furan with α-ketimino esters induced by a conjugated double hydrogen bond network of chiral bis(phosphoric acid) catalysts Reviewed

    Manabu Hatano, Haruka Okamoto, Taro Kawakami, Kohei Toh, Hidefumi Nakatsuji, Akira Sakakura, Kazuaki Ishihara

    Chemical Science   9 ( 30 )   6361 - 6367   2018

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    <p>Chiral <italic>C</italic>2- and <italic>C</italic>1-symmetric BINOL-derived bis(phosphoric acid) catalysts facilitated the enantioselective aza-Friedel–Crafts reaction of 2-methoxyfuran with α-ketimino esters.</p>

    DOI: 10.1039/C8SC02290A

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  • REGIOSELECTIVE DMAD-INSERTION REACTION OF SILYL DIENOL ETHER OF gamma-PYRONE UNDER CATALYST- AND HEATING-FREE CONDITIONS Reviewed

    Ichiro Hayakawa, Yuji Yamanaka, Koichi Mitsudo, Hiromi Ota, Akira Sakakura

    HETEROCYCLES   94 ( 12 )   2299 - 2306   2017.12

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    The reaction of silyl dienol ether of gamma-pyrone with dimethyl acetylenedicarboxylate (DMAD) gives the regioselective insertion product in 66% yield. This DMAD-insertion reaction is thought to include a three-step sequence: (1) thermal [2+2]-type cycloaddition reaction of silyl dienol ether of gamma-pyrone with DMAD, (2) ring-opening electrocyclic reaction of the cyclobutene skeleton, and (3) hydrolysis of the silyl dienol ether. The present reaction proceeds under mild conditions without any catalysts or heating. In addition, the [2+2]-type cycloaddition reaction proceeds regioselectively at the C3-C4 double bond in the silyl dienol ether of gamma-pyrone.

    DOI: 10.3987/COM-17-13820

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  • Diastereodivergent Henry Reaction for the Stereoselective Construction of Nitrogen-Containing Tetrasubstituted Carbons: Application to Total Synthesis of Manzacidins A and C Reviewed

    Takayuki Kudoh, Yuya Araki, Natsumi Miyoshi, Mizuho Tanioka, Akira Sakakura

    ASIAN JOURNAL OF ORGANIC CHEMISTRY   6 ( 12 )   1760 - 1763   2017.12

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    beta,beta,-Disubstituted -amino alcohols has been synthesized in a diastereodivergent manner from chiral secondary nitroalkanes as starting materials. In this key Henry reaction, the use of different protecting groups resulted in the diastereoselective construction of the tetrasubstituted carbon stereocenter with different configuration. Based on this methodology, a total synthesis of manzacidins A and C has been achieved.

    DOI: 10.1002/ajoc.201700568

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  • Heat Versus Basic Conditions: Intramolecular Dehydro-Diels-Alder Reaction of 1-Indolyl-1,6-heptadiynes for the Selective Synthesis of Substituted Carbazoles Reviewed

    Takayuki Kudoh, Syo Fujisawa, Megumi Kitamura, Akira Sakakura

    SYNLETT   28 ( 16 )   2189 - 2193   2017.10

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    The intramolecular dehydro-Diels-Alder reaction of 1-indolyl-1,6-heptadiynes proceeds smoothly under rather mild heating conditions to give substituted carbazoles in moderate to good yields. The reaction of 7-aryl-1-indolyl-1,6-heptadiynes under heating gives the corresponding carbazoles chemoselectively in high yields, whereas the reaction under basic conditions gives naphthalenes as major products.

    DOI: 10.1055/s-0036-1588461

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  • Reinvestigation of the Biomimetic Cyclization of 3,5-Diketo Esters: Application to the Total Synthesis of Cyercene A, an alpha-Methoxy-gamma-Pyrone-Containing Polypropionate Reviewed

    Kai Onda, Ichiro Hayakawa, Akira Sakakura

    SYNLETT   28 ( 13 )   1596 - 1600   2017.8

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    The biomimetic cyclization of 3,5-diketo esters was reinvestigated for the synthesis of alpha-methoxy-gamma-pyrones. 3,5-Diketo esters were selectively synthesized via the aldol reaction of commercially available methyl 2-methyl-3-oxopentanoate with an aldehyde followed by the oxidation with AZADOL (R) and PhI(OAc)(2). The DBU-promoted intramolecular transesterification of 3,5-diketo esters showed excellent reactivity in MeOH, to give the corresponding gamma-hydroxy-alpha-pyrones in high yields under mild reaction conditions. Based on the present cyclization scheme, the total synthesis of cyercene A was achieved.

    DOI: 10.1055/s-0036-1588795

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  • Discovery of O-6-benzyl glaziovianin A, a potent cytotoxic substance and a potent inhibitor of alpha,beta-tubulin polymerization Reviewed

    Ichiro Hayakawa, Shuya Shioda, Takumi Chinen, Taisei Hatanaka, Haruna Ebisu, Akira Sakakura, Takeo Usui, Hideo Kigoshi

    BIOORGANIC & MEDICINAL CHEMISTRY   24 ( 21 )   5639 - 5645   2016.11

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

    We have discovered O-6-benzyl glaziovianin A, which showed stronger inhibition of microtubule polymerization (IC50 = 2.1 mu M) than known alpha,beta-tubulin inhibitors, such as colchicine and glaziovianin A. Also, we performed competition binding experiments of O-6-benzyl glaziovianin A and revealed that O-6-benzyl glaziovianin A binds to the colchicine binding site with high affinity. It is interesting that glaziovianin A derivatives change their mode of action in benzylation at the O-6 (alpha,beta-tubulin inhibitor) or O-7 (gamma-tubulin-specific inhibitor) position. (C) 2016 Elsevier Ltd. All rights reserved.

    DOI: 10.1016/j.bmc.2016.09.026

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  • A short access to 3,5-disubstituted piperazinones based on the aza-Michael addition of alpha-amino esters to beta-substituted nitroalkenes Reviewed

    Takayuki Kudoh, Seiji Isoyama, Sachiko Kagimoto, Katsutoshi Kurihara, Akira Sakakura

    TETRAHEDRON LETTERS   57 ( 42 )   4693 - 4696   2016.10

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    A simple procedure for the synthesis of chiral 3,5-disubstituted piperazinones is described. The aza-Michael addition of alpha-amino esters to beta-substituted nitroalkenes in an organic/aqueous biphasic solvent system followed by reduction of a nitro group with zinc nanopowder in acidic media and intramolecular ester-amide exchange under heating conditions gives piperazinones in good overall yields. This novel three-step process can provide a short access to a variety of chiral 3,5-disubstituted piperazinones simply by changing the combination of starting nitroalkenes and alpha-amino esters. This process can be applied to the concise synthesis of the piperazinone-containing natural product 6',6 ''-didebromo-cis-3,4-dihydrohamacanthin B. (C) 2016 Elsevier Ltd. All rights reserved.

    DOI: 10.1016/j.tetlet.2016.09.015

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  • Enantioselective bromocyclization of 2-geranylphenols induced by chiral phosphite-urea bifunctional catalysts Reviewed

    Yasuhiro Sawamura, Yoshihiro Ogura, Hidefumi Nakatsuji, Akira Sakakura, Kazuaki Ishihara

    CHEMICAL COMMUNICATIONS   52 ( 36 )   6068 - 6071   2016

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    Authorship:Corresponding author   Language:English   Publishing type:Research paper (scientific journal)   Publisher:ROYAL SOC CHEMISTRY  

    Chiral phosphite-urea bifunctional catalysts have been developed for the enantioselective bromocyclization of 2-geranylphenols with N-bromophthalimide (NBP) for the first time. The chiral triaryl phosphite moiety activates NBP to generate a bromophosphonium ion. On the other hand, the urea moiety interacts with a hydroxyl group of the substrate through hydrogen bonding interactions. Enantioselectivity is effectively induced through two-point attractive interactions between the catalyst and the substrate.

    DOI: 10.1039/c6cc00229c

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  • Stereoselective Electrophilic Cyclization Reviewed

    Akira Sakakura, Kazuaki Ishihara

    CHEMICAL RECORD   15 ( 4 )   728 - 742   2015.8

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    Authorship:Lead author, Corresponding author   Language:English   Publisher:WILEY-V C H VERLAG GMBH  

    Electrophilic cyclizations of unactivated alkenes play highly important roles in the synthesis of useful building blocks. This account describes our contributions to the rational design of monofunctionalized chiral Lewis base catalysts for enantioselective iodo- and protocyclizations. For the stereoselective promotion of electrophilic bromocyclizations, nucleophilic phosphite-urea cooperative catalysts have been designed.

    DOI: 10.1002/tcr.201500005

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  • Enantioselective 1,3-Dipolar Cycloaddition of Azomethine Imines with Propioloylpyrazoles Induced by Chiral pi-Cation Catalysts Reviewed

    Masahiro Hori, Akira Sakakura, Kazuaki Ishihara

    JOURNAL OF THE AMERICAN CHEMICAL SOCIETY   136 ( 38 )   13198 - 13201   2014.9

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

    We developed 1,3-dipolar cycloadditions of azomethine imines with propioloylpyrazoles catalyzed by a chiral copper(II) complex of 3-(2-naphthyl)-L-alanine amide. The asymmetric environment created by intramolecular pi-cation interaction and the N-alkyl group of the chiral ligand gives the corresponding adducts in high yields with excellent enantioselectivity. This is the first successful method for the catalytic enantioselective 1,3-dipolar cycloaddition of azomethine imines with internal alkyne derivatives to give fully substituted pyrazolines.

    DOI: 10.1021/ja508441t

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  • Selective Bromocyclization of 2-Geranylphenols Promoted by Phosphite-Urea Cooperative Catalysts Reviewed

    Yasuhiro Sawamura, Hidefumi Nakatsuji, Matsujiro Akakura, Akira Sakakura, Kazuaki Ishihara

    CHIRALITY   26 ( 7 )   356 - 360   2014.7

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    Nucleophilic phosphite-urea cooperative catalysts are highly efficient for the bromonium-induced cyclization of 2-geranylphenols. Phosphite-N,N'-dimethylurea catalysts also show moderate activity, probably due to the steric effect of their bent conformation. Chirality 26:355-359, 2014. (c) 2014 Wiley Periodicals, Inc.

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  • Cooperative Activation with Chiral Nucleophilic Catalysts and N-Haloimides: Enantioselective Iodolactonization of 4-Arylmethyl-4-pentenoic Acids Reviewed

    Hidefumi Nakatsuji, Yasuhiro Sawamura, Akira Sakakura, Kazuaki Ishihara

    ANGEWANDTE CHEMIE-INTERNATIONAL EDITION   53 ( 27 )   6974 - 6977   2014.7

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    Chiral triaryl phosphates promote the enantioselective iodolactonization of 4-substituted 4-pentenoic acids to give the corresponding iodolactones in high yields with high enantioselectivity. N-Chlorophthalimide (NCP) is employed as a Lewis acidic activator and oxidant of I-2 for the present iodolactonization. In combination with 1.5 equivalents of NCP, only 0.5 equivalents of I-2 are sufficient to generate the iodinating reagent.

    DOI: 10.1002/anie.201400946

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  • Catalytic Enantioselective Inverse Electron Demand Hetero-Diels-Alder Reaction with Allylsilanes Reviewed

    Yuki Matsumura, Takahiro Suzuki, Akira Sakakura, Kazuaki Ishihara

    ANGEWANDTE CHEMIE-INTERNATIONAL EDITION   53 ( 24 )   6131 - 6134   2014.6

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    The first diastereo- and enantioselective inverse electron demand hetero-Diels-Alder reaction of beta,gamma-unsaturated alpha-ketoesters with allylsilanes is described. Chiral copper( II) catalysts successfully activate the beta,gamma-unsaturated alpha-ketoesters and promote the reaction with allylsilanes with excellent enantioselectivities. This process represents a new entry to chiral oxanes.

    DOI: 10.1002/anie.201402934

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  • Enantioselective Cyanoethoxycarbonylation of Isatins Promoted by a Lewis Base-Bronsted Acid Cooperative Catalyst Reviewed

    Yoshihiro Ogura, Matsujiro Akakura, Akira Sakakura, Kazuaki Ishihara

    ANGEWANDTE CHEMIE-INTERNATIONAL EDITION   52 ( 32 )   8299 - 8303   2013.8

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    DOI: 10.1002/anie.201303572

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  • Primary Alkylboronic Acids as Highly Active Catalysts for the Dehydrative Amide Condensation of alpha-Hydroxycarboxylic Acids Reviewed

    Risa Yamashita, Akira Sakakura, Kazuaki Ishihara

    ORGANIC LETTERS   15 ( 14 )   3654 - 3657   2013.7

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    Primary alkylboronic acids such as methyl boronic acid and butylboronic acid are highly active catalysts for the dehydrative amide condensation of alpha-hydroxycarboxylic acids. The catalytic activities of these primary alkylboronic acids are much higher than those of the previously reported arylboronic acids. The present method was easily applied to a large-scale synthesis, and 14 g of an amide was obtained in a single reaction.

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  • Kinetic Resolution of Racemic Carboxylic Acids through Asymmetric Protolactonization Promoted by Chiral Phosphonous Acid Diester Reviewed

    Masayuki Sakuma, Akira Sakakura, Kazuaki Ishihara

    ORGANIC LETTERS   15 ( 11 )   2838 - 2841   2013.6

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    Chiral phosphonium salts induce the kinetic resolution of racemic a-substituted unsaturated carboxylic acids through asymmetric protolactonization. Both the lactones and the recovered carboxylic acids are obtained with high enantioselectivities and high S (=k(fast)/k(slow)) values. Asymmetric protolactonization also leads to the desymmetrization of achiral carboxylic acids. Notably, chiral phosphonous acid diester not only induced the enantioselectivity but also promoted protolactonization.

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  • "Phosphite-urea" cooperative high-turnover catalysts for the highly selective bromocyclization of homogeranylarenes Reviewed

    Yasuhiro Sawamura, Hidefumi Nakatsuji, Akira Sakakura, Kazuaki Ishihara

    CHEMICAL SCIENCE   4 ( 11 )   4181 - 4186   2013

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    Nucleophilic phosphite-urea cooperative high-turnover catalysts have been designed for the highly selective bromocyclization of homogeranylarenes. The introduction of a urea moiety and bulky aryl groups in the catalyst inhibits decomposition of the catalyst and the generation of byproducts. Only 0.5 mol% of the catalyst successfully promotes the bromocyclization of 4-homogeranyltoluene to give the desired product in 96% yield.

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  • alpha-Heterosubstituted beta-Alkylacroleins as Useful Multisubstituted Dienophiles for Enantioselective Diels-Alder Reactions Reviewed

    Akira Sakakura, Hiroki Yamada, Kazuaki Ishihara

    ASIAN JOURNAL OF ORGANIC CHEMISTRY   1 ( 2 )   133 - 137   2012.10

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    DOI: 10.1002/ajoc.201200054

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  • Enantioselective Diels-Alder Reaction of alpha-(Acylthio)acroleins: A New Entry to Sulfur-Containing Chiral Quaternary Carbons Reviewed

    Akira Sakakura, Hiroki Yamada, Kazuaki Ishihara

    ORGANIC LETTERS   14 ( 12 )   2972 - 2975   2012.6

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    A catalytic and enantioselective Diels-Alder reaction of alpha-(carbamoylthio)acroleins induced by an organoammonium salt of chiral triamine is described. alpha-(Carbamoylthio)acroleins are designed and synthesized as new sulfur-containing dienophiles for the first time. The Diels-Alder reaction affords chiral tertiary thiol precursors with up to 91% ee.

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  • N,N-Diarylammonium Pyrosulfate as a Highly Effective Reverse Micelle-Type Catalyst for Hydrolysis of Esters Reviewed

    Yoshiki Koshikari, Akira Sakakura, Kazuaki Ishihara

    ORGANIC LETTERS   14 ( 12 )   3194 - 3197   2012.6

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    Reverse micelle-type N,N-diarylammonium pyrosulfate (3-5 mol %) efficiently catalyzes the hydrolysis of esters (up to 100 mmol scale) under organic solvent-free conditions. The present method is successfully applied to the hydrolysis of various esters without the decomposition of the base-sensitive moieties and without any loss of optical purity for alpha-heterosubstituted carboxylic acids.

    DOI: 10.1021/ol301290c

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  • Hydrophobic N,N-Diarylammonium Pyrosulfates as Dehydrative Condensation Catalysts under Aqueous Conditions Reviewed

    Akira Sakakura, Yoshiki Koshikari, Matsujiro Akakura, Kazuaki Ishihara

    ORGANIC LETTERS   14 ( 1 )   30 - 33   2012.1

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    Oil-soluble N,N-diarylammonium pyrosulfates as nonsurfactant-type catalysts for the dehydrative ester condensation under aqueous conditions are described. Preheat treatment of dibasic sulfuric acid with bulky N,N-diarylamines generates water-tolerant salts of pyrosulfuric acid as active catalyst species. The present catalysts in water can also widely be applied to unusual selective esterifications and dehydrative glycosylation.

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  • Aplyronines D-H from the sea hare Aplysia kurodai: isolation, structures, and cytotoxicity Reviewed

    Makoto Ojika, Hideo Kigoshi, Kiyotake Suenaga, Yoshifumi Imamura, Kohji Yoshikawa, Takeshi Ishigaki, Akira Sakakura, Tsuyoshi Mutou, Kiyoyuki Yamada

    TETRAHEDRON   68 ( 4 )   982 - 987   2012.1

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    Five cytotoxic macrolides. aplyronines D-H (4-8), were isolated from the Japanese sea hare Aplysia kurodai. They are new congeners of the antitumor compound aplyronine A (1), which was previously isolated from the same organism. Their structures were determined by spectroscopic analysis (NMR and MS). The cytotoxicity of these new compounds was evaluated in comparison with that of aplyronines A C (1-3), suggesting the importance of the 7-O-seryl ester group for mediating the potent cytotoxicity of aplyronines. (C) 2011 Elsevier Ltd. All rights reserved.

    DOI: 10.1016/j.tet.2011.11.095

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  • Desymmetrization of meso-Glycerol Derivatives Induced by L-Histidine-Derived Acylation Catalysts Reviewed

    Akira Sakakura, Shuhei Umemura, Kazuaki Ishihara

    ADVANCED SYNTHESIS & CATALYSIS   353 ( 11-12 )   1938 - 1942   2011.8

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    The desymmetrization of meso-glycerol derivatives bearing a 3-pyrroline-1-carbonyl (Pyroc) directing group is demonstrated through an enantioselective acylation reaction promoted by L-histidine-derived bifunctional catalysts. The desired monoacylated products are obtained in good yields (up to 74%) with high enantioselectivities (up to 99% ee).

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  • Chiral Lewis Base-Assisted Brønsted Acid (LBBA)-Catalyzed Enantioselective Cyclization of 2-Geranylphenols Reviewed

    Akira Sakakura, Masayuki Sakuma, Kazuaki Ishihara

    ORGANIC LETTERS   13 ( 12 )   3130 - 3133   2011.6

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    DOI: 10.1021/ol201032t

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  • Bronsted Base-Assisted Boronic Acid Catalysis for the Dehydrative Intramolecular Condensation of Dicarboxylic Acids Reviewed

    Akira Sakakura, Takuro Ohkubo, Risa Yamashita, Matsujiro Akakura, Kazuaki Ishihara

    ORGANIC LETTERS   13 ( 5 )   892 - 895   2011.3

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    Bronsted base-assisted boronic acid catalysis for the dehydrative self-condensation of carboxylic acids is described. Arylboronic acid bearing bulky (N,N-dialkylamino)methyl groups at the 2,6-positions can catalyze the intramolecular dehydrative condensation of di- and tetracarboxylic acids. This is the first successful method for the catalytic dehydrative self-condensation of carboxylic acids.

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  • Intramolecular Dehydrative Condensation of Dicarboxylic Acids with Bronsted Base-Assisted Boronic Acid Catalysts Reviewed

    Akira Sakakura, Risa Yamashita, Takuro Ohkubo, Matsujiro Akakura, Kazuaki Ishihara

    AUSTRALIAN JOURNAL OF CHEMISTRY   64 ( 11 )   1458 - 1465   2011

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    Bifunctional Bronsted base-assisted boronic acid catalysts, arylboronic acids bearing two sterically bulky (N,N-dialkylamino)methyl groups at the 2,6-positions, exhibit remarkable activities for the dehydrative intramolecular condensation of dicarboxylic acids. The steric bulkiness of the (N,N-dialkylamino) methyl groups of 1, which prevents the formation of less active species such as the N -> B chelated species and triarylboroxines 3, is crucial for the high catalytic activity. This is the first successful method for the catalytic dehydrative self-condensation of di- and tetracarboxylic acids.

    DOI: 10.1071/CH11301

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  • Asymmetric Cu(II) catalyses for cycloaddition reactions based on pi-cation or pi-cation interactions Reviewed

    Akira Sakakura, Kazuaki Ishihara

    CHEMICAL SOCIETY REVIEWS   40 ( 1 )   163 - 172   2011

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    The rational design of small but highly functional artificial catalysts is very important for practical organic synthesis. Asymmetric Lewis acid catalyses with non-covalent secondary interactions have been developed for enantioselective reactions. This tutorial review describes the concept, design and examples of asymmetric Cu(II) catalyses for cycloaddition reactions based on intramolecular pi-cation or pi-cation interactions between the copper( II) cation and auxiliary Lewis basic sites of the chiral ligands.

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  • NUCLEOPHILIC PHOSPHINE-CATALYZED IODOCYCLIZATION OF ISOPRENOIDS BEARING AN OXYGEN TERMINAL GROUP Reviewed

    Akira Sakakura, Gakujun Shomi, Atsushi Ukai, Kazuaki Ishihara

    HETEROCYCLES   82 ( 1 )   249 - 255   2010.12

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    The nucleophilic phosphine-catalyzed diastereoselective iodocyclization of linear isoprenoids bearing an oxygen terminal group was investigated. TBDMS ether of homogeraniol and TBDMS ester of homogeranic acid were successfully converted to the corresponding iodopolycyclic products in the presence of a catalytic amount of triphenylphosphine with complete diastereoselectivity.

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  • Catalytic Enantioselective 1,3-Dipolar Cycloadditions of Nitrones with Propioloylpyrazoles and Acryloylpyrazoles Induced by Chiral pi-Cation Catalysts Reviewed

    Akira Sakakura, Masahiro Hori, Makoto Fushimi, Kazuaki Ishihara

    JOURNAL OF THE AMERICAN CHEMICAL SOCIETY   132 ( 44 )   15550 - 15552   2010.11

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    A chiral copper(II) complex of 3-(2-naphthyl)-L-alanine amide successfully catalyzes the enantioselective 1,3-dipolar cycloaddition reaction of nitrones with propioloylpyrazole and acryloylpyrazole derivatives. The asymmetric environment created by intramolecular pi-cation interaction gives the corresponding adducts in high yields with excellent enantioselectivity. This is the first successful method for the catalytic enantioselective 1,3-dipolar cycloaddition of nitrones with acetylene derivatives. The 1,3-dipolar cycloadducts can be stereoselectively converted to beta-lactams via reductive cleavage of the N-O bond using SmI2.

    DOI: 10.1021/ja1081603

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  • Organoammonium Salt-Catalyzed Enantioselective Cycloaddition Reactions with alpha-(Acyloxy)- or alpha-Diacylaminoacroleins Reviewed

    Akira Sakakura, Kazuaki Ishihara

    BULLETIN OF THE CHEMICAL SOCIETY OF JAPAN   83 ( 4 )   313 - 322   2010.4

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    The rational design of small-molecule chiral catalysts is an important subject in the development of practical organic syntheses. We have designed primary ammonium salt catalysts for enantioselective cycloaddition reactions with alpha-substituted acroleins such as alpha-(acyloxy)acroleins and alpha-diacylaminoacroleins. Ammonium salts of an aliphatic triamine derived from H-L-Phe-L-Leu-N(CH2CH2)(2) successfully promote the Diels-Alder reaction of alpha-(acyloxy)acroleins and alpha-(N,N-diacylamino)acroleins, and the [2 + 2] cycloaddition reaction of alpha-(acyloxy)acroleins with high enantioselectivity. An ammonium salt of a C-2-symmetric aromatic diamine, 1,1'-binaplithy1-2,2'-diamine, with a superacid is also an efficient catalyst and shows high activity and enantioselectivity for the Diels Alder reaction of cyclic dienes with alpha-(acyloxy)acroleins.

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  • Rational Design of Highly Effective Asymmetric Diels-Alder Catalysts Bearing 4,4 '-Sulfonamidomethyl Groups Reviewed

    Akira Sakakura, Rei Kondo, Yuki Matsumura, Matsujiro Akakura, Kazuaki Ishihara

    JOURNAL OF THE AMERICAN CHEMICAL SOCIETY   131 ( 49 )   17762 - 17764   2009.12

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    DOI: 10.1021/ja906098b

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  • 3-Pyrroline-1-carbonyl (Pyroc) Group: A Removable Protecting Group for the Kinetic Resolution of Racemic Carboxylic Acids and Alcohols through Catalytic Asymmetric Acylation Reviewed

    Akira Sakakura, Shuhei Umemura, Kazuaki Ishihara

    SYNLETT   ( 10 )   1647 - 1650   2009.6

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    The O-3-pyrroline-1-carbonyl (O-Pyroc) group and 3-pyrrolinamide are useful removable protecting groups for the kinetic resolution of racemic alpha-hydroxycarboxylic acids, beta-hydroxycarboxylic acids, 1,2-dicarboxylic acids, and 1,2-diols using the L-histidine-derived bifunctional catalysts. The Pyroc group can be easily introduced from Pyroc chloride. Selective deprotection of the Pyroc group and 3-pyrrolinamide can be carried out via DDQ oxidation followed by hydrolysis using sodium hydroxide, without epimerization.

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  • Dehydrative cyclization of serine, threonine, and cysteine residues catalyzed by molybdenum(VI) oxo compounds Reviewed

    Akira Sakakura, Rei Kondo, Shuhei Umemura, Kazuaki Ishihara

    TETRAHEDRON   65 ( 10 )   2102 - 2109   2009.3

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    Commercially available molybdenum(VI) oxides such as (NH4)(2)MoO4, (NH4)(6)Mo7O24 center dot 4H(2)O, MoO2(acac)(2), and MoO2(TMHD)(2) are highly effective dehydrative cyclization catalysts for the synthesis of a variety of oxazolines. The reaction proceeds with a complete retention of configuration at the beta-position. For the dehydrative cyclization of cysteine derivatives, bis(2-ethyl-8-quinolinolato)dioxomolybdenum(VI) shows remarkable catalytic activity and gives thiazolines without a significant loss of stereochemical integrity at the C2-exomethine positions. (C) 2008 Elsevier Ltd. All rights reserved.

    DOI: 10.1016/j.tet.2008.12.074

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  • Design of High-Performance Catalysts Based on Acid-Base Combined Salts and Development of Highly Selective Reactions Reviewed

    Akira Sakakura

    JOURNAL OF SYNTHETIC ORGANIC CHEMISTRY JAPAN   66 ( 10 )   942 - 952   2008.10

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    The design of highly functionalized artificial catalysts is very important for practical organic synthesis. We have succeeded in the rational design of high-performance catalysts based on acid-base combined salts. Acid-base combined salt catalysts can be classified into three types: (1) Metal oxide-Lewis base combined salts, (2) Bronsted acid-Bronsted base combined salts, and (3) Lewis acid-Lewis base combined salts. Here we report our recent studies on development of highly selective cyclization reactions for the synthesis of key intermediates of bioactive natural products. Molybdenum(VI) oxide-bis(quinolinolato) complexes (class 1) efficiently catalyze biomimetic dehydrative cyclization of serine, threonine and cysteine derivatives to give oxazolines and thiazolines. Chiral 1,1'-binaphthyl-2,2'-diammonium salts (class 2) are useful catalysts for enantioselective Diels-Alder reaction of alpha-acyloxyacroleins. We also have developed the first enantioselective biomimetic iodocyclization of isoprenoids using a chiral nucleophilic promoter (class 3).

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  • SELECTIVE SYNTHESIS OF CYCLIC PHOSPHORIC ACID DIESTERS THROUGH OXORHENIUM(VII)-CATALYZED DEHYDRATIVE CONDENSATION OF PHOSPHORIC ACID WITH ALCOHOLS Reviewed

    Akira Sakakura, Masayuki Sakuma, Mikimoto Katsukawa, Kazuaki Ishihara

    HETEROCYCLES   76 ( 1 )   657 - 665   2008.9

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    The selective synthesis of phosphoric acid diesters has been achieved through the direct catalytic dehydrative condensation of phosphoric acid with two equivalents of alcohols. The present method works especially well for the synthesis of cyclic phosphoric acid diesters. The combination of perrhenic acid and N-methylbenzylamine efficiently catalyzes the dehydrative condensation of phosphoric acid with equimolar amounts of diols to give cyclic phosphoric acid diesters in excellent yields.

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  • Kinetic resolution of racemic carboxylic acids by an L-histidine-derived sulfonamide-induced enantioselective esterification reaction Reviewed

    Kazuaki Ishihara, Yuji Kosugi, Shuhei Umemura, Akira Sakakura

    ORGANIC LETTERS   10 ( 15 )   3191 - 3194   2008.8

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    The direct and catalytic kinetic resolution of racemic carboxylic acids bearing a Bronsted base such as O-protected alpha-hydroxy carboxylic acids and N-protected alpha-amino acids has been accomplished through an L-histidine-derived sulfonamide-induced enantioselective esterification reaction with tert-butyl alcohol for the first time. Highly asymmetric induction [S(k(fast)/k(slow)) = up to 56] has been achieved under the equilibrium between a chiral catalyst and two diastereomeric acylammonium salts through an intramolecular hydrogen-bonding interaction.

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  • Open-air and solvent-free ester condensation catalyzed by sulfonic acids Reviewed

    Akira Sakakura, Yoshiki Koshikari, Kazuaki Ishihara

    TETRAHEDRON LETTERS   49 ( 34 )   5017 - 5020   2008.8

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    Ester condensation is one among the most fundamental organic transformations, and more environmentally benign alternatives to current esterification processes are needed. Under solvent-free and drying agent-free conditions, catalytic amounts of sulfonic acids promote ester condensation between an equimolar mixture of carboxylic acids and alcohols. In particular, p-toluenesulfonic acid (TsOH) and 10-camphorsulfonic acid (CSA), which have appropriate acidities, efficiently catalyze the ester condensation of secondary alcohols without their decomposition. Since the present protocol does not require solvents under simple open-air conditions, a large amount of esters can be synthesized in a rather small apparatus. (c) 2008 Elsevier Ltd. All rights reserved.

    DOI: 10.1016/j.tetlet.2008.06.058

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  • Rate-accelerating effect by the neighboring-group participation of protecting groups in the dehydrative cyclization of 1,3,5-triketones Reviewed

    Akira Sakakura, Hitoshi Watanabe, Kazuaki Ishihara

    ORGANIC LETTERS   10 ( 12 )   2569 - 2572   2008.6

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    Neighboring-group participation of an acyl protecting group efficiently promotes the Bronsted acid-catalyzed dehydrative cyclization of 1,3,5-triketones to gamma-pyrones, whereas a bulky silyloxy group in the beta-position retards the cyclization. This reaction provides an efficient synthetic route for a common intermediate for the synthesis of gamma-pyrone-containing bioactive natural products.

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  • Convergent total syntheses of fluvibactin and vibriobactin using molybdenum(VI) oxide-catalyzed dehydrative cyclization as a key step Reviewed

    Akira Sakakura, Shuhei Umemura, Kazuaki Ishihara

    CHEMICAL COMMUNICATIONS   ( 30 )   3561 - 3563   2008

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    Efficient total syntheses of fluvibactin and vibriobactin have been achieved via molybdenum(VI) oxide-catalyzed dehydrative cyclization, Sb(OEt)(3)-catalyzed ester-amide transformation, and WSCI and HOAt-promoted dehydrative amide formation.

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  • Widely useful DMAP-catalyzed esterification under auxiliary base- and solvent-free conditions Reviewed

    Akira Sakakura, Kirnio Kawajiri, Takuro Ohkubo, Yuji Kosugi, Kazuaki Ishihara

    JOURNAL OF THE AMERICAN CHEMICAL SOCIETY   129 ( 47 )   14775 - 14779   2007.11

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    With regard to atom economy and E-factor, catalytic condensation of carboxylic acids with equimolar amounts of alcohols is the most desirable. Although several highly active dehydration catalysts have been reported, more efficient alternatives are still strongly needed because the dehydrative esterification of tertiary alcohols, phenols, acid-sensitive alcohols, amino acids, and hardly soluble alcohols has never proceeded satisfactorily. Here we report new insights into the classical DMAP-catalyzed acylation of alcohols: surprisingly, only a 0.05-2 mol % of DMAP can efficiently promote acylation of alcohols with acid anhydrides under auxiliary base- and solvent-free conditions to give the corresponding esters in high yields. Furthermore, we achieved the recovery and reuse of Commercially available polystyrene-supported DMAP without using any solvents. These serendipitous findings provide widely useful and environmentally benign esterification methods, which might be more practical and reliable than catalytic dehydrative condensation methods, in particular, for the less reactive alcohols which hardly condense with carboxylic acid directly.

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  • Enantioselective biomimetic polyene cyclization of polyprenoids - Long-sought enantioselective reaction induced by a "chiral halonium ion" Reviewed

    Akira Sakakura, Kazuaki Ishihara

    CHIMICA OGGI-CHEMISTRY TODAY   25 ( 5 )   9 - 12   2007.9

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    Enantioselective biomimetic polyene cyclizations of polyprenoids have been studied for a long time. Very recently, we have developed the first "chiral iodonium ion"-induced enantioselective polyene cyclization of polyprenoids using a nucleophilic promoter. Achiral nucleophilic phosphorus compounds catalytically promote the diastereoselective halocyclization in dichloromethane to give a halogenated cyclic product in excellent yield. Moreover, chiral phosphoramidites stoichiometrically promote the enantioselective halocyclization of simple polyprenoids with N-iodosuccinimide in toluene to give iodinated cyclic products in up to 99 percent ee and 99 percent ds. Some enantioselective polycyclizations have been reported in addition to this halocyclization. One of the advantages of these biomimetic polycyclizations is the simultaneous formation of several carbon-carbon bonds with the relative and absolute stereocontrol. Enantioselective biomimetic domino reactions would be highly useful for the practical synthesis of natural products and related compounds.

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  • Catalytic synthesis of peptide-derived thiazolines and oxazolines using Bis(quinolinolato)dioxomolybdenum(VI) complexes Reviewed

    Akira Sakakura, Rei Kondo, Shuhei Umemura, Kazuaki Ishihara

    ADVANCED SYNTHESIS & CATALYSIS   349 ( 10 )   1641 - 1646   2007.7

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    Bis(2-ethyl-8-quinolinolato)dioxomolybdenum(VI) (9) (1 mol%) shows remarkable catalytic activity for the dehydrative cyclization of cysteine-containing dipeptides 1 to give the corresponding thiazolines 2 with less than 6% epimerization at the C2-exomethine position. For the dehydrative cyclization of threonine-containing dipeptides 4, 1 mol% of bis(2-phenyl-8-quinolinolato)dioxomolybdenum(VI) (10) gives the corresponding oxazolines 5 with retention of configuration at the 5-position.

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  • Dehydrative cyclization catalyzed by the combination of molybdenum(VI) oxides and benzoic acids: First synthesis of the antitumour substance BE-70016 Reviewed

    Akira Sakakura, Shuhei Umemura, Rei Kondo, Kazuaki Ishihara

    ADVANCED SYNTHESIS & CATALYSIS   349 ( 4-5 )   551 - 555   2007.3

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    The dehydrative cyclization of N-(o-hydroxybenzoyl)threonine derivative la is efficiently promoted by the combined use of molybdenum(VI) oxides and benzoic acids bearing electron-withdrawing substituents. In the presence of ammonium molybdate [(NH4)(2)MoO4, 10 mol %] and pentafluorobenzoic acid (C6F5CO2H; 10 mol %), dehydrative cyclization of la was conducted in toluene under azeotropic reflux conditions to give 2-(o-hydroxyphenyl)oxazoline 2a in 76 % yield. Furthermore, the first total synthesis of the antitumour substance BE-70016 was achieved using the catalytic dehydrative cyclization of la as a key reaction.

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  • Design of highly functional small-molecule catalysts and related reactions based on acid-base combination chemistry Reviewed

    Kazuaki Ishihara, Akira Sakakura, Manabu Hatano

    SYNLETT   ( 5 )   686 - 703   2007.3

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    The design of small but highly functional artificial catalysts is very important for practical organic synthesis. We have succeeded in the rational design of small and simple catalysts and related reactions based on acid-base combination chemistry. Acid-base combined catalysts can be classified into three types: (i) acid-base combined salt catalysts, (ii) conjugate acid-base catalysts, and (iii) nonconjugate acid-base catalysts. We have systematically developed acid-base combined salt catalysts such as ammonium salts, ate complexes, ion pairs and cation-pi complexes, acid-base conjugate catalysts such as metal oxides (monoconjugation) and zinc(Il)3,3'-diphosphinol-BINOLates (triconjugation), and acid-base nonconjugate catalysts like L-histidine-derived sulfonamides.

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  • Enantioselective halocyclization of polyprenoids induced by nucleophilic phosphoramidites Reviewed

    Akira Sakakura, Atsushi Ukai, Kazuaki Ishihara

    NATURE   445 ( 7130 )   900 - 903   2007.2

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    Polycyclic bio-active natural products that contain halogen atoms have been isolated from a number of different marine organisms(1). The biosynthesis of these natural products appears to be initiated by an electrophilic halogenation reaction at a carbon - carbon double bond(2-4) via a mechanism that is similar to a proton-induced olefin polycyclization(5-8). Enzymes such as haloperoxidases generate an electrophilic halonium ion ( or its equivalent), which reacts with the terminal carbon - carbon double bond of the polyprenoid, enantioselectively inducing a cyclization reaction that produces a halogenated polycyclic terpenoid. Use of an enantioselective halocyclization reaction is one possible way to chemically synthesize these halogenated cyclic terpenoids; although several brominated cyclic terpenoids have been synthesized via a diastereoselective halocyclization reaction that uses stoichiometric quantities of a brominating reagent(9-12), the enantioselective halocyclization of isoprenoids induced by a chiral promoter has not yet been reported. Here we report the enantioselective halocyclization of simple polyprenoids using a nucleophilic promoter. Achiral nucleophilic phosphorus compounds are able to promote the diastereoselective halocyclization reaction to give a halogenated cyclic product in excellent yields. Moreover, chiral phosphoramidites promote the enantioselective halocyclization of simple polyprenoids with N-iodosuccinimide to give iodinated cyclic products in up to 99% enantiomeric excess and diastereomeric excess. To the best of our knowledge, this is the first successful example of the enantioselective halopolycyclization of polyprenoids.

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  • Unusual rate acceleration in bronsted acid catalyzed dehydration reactions: Local hydrophobic environment in aggregated N-(2,6-diphenylphenyl)-N-mesitylammonium pentafluorobenzenesulfonates Reviewed

    Akira Sakakura, Hitoshi Watanabe, Shoko Nakagawa, Kazuaki Ishihara

    CHEMISTRY-AN ASIAN JOURNAL   2 ( 4 )   477 - 483   2007

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    Bulky diarylammonium pentafluorobenzenesulfonates effectively promote dehydration reactions, such as condensation reactions to give esters and the dehydrative cyclization of 1,3.5-triketones. In particular, N-(2,6-diphenylphenyl)-N-mesitylammonium pentafluorobenzenesulfonate shows much higher catalytic activity than C6F5SO3H under reaction conditions without the removal of generated water, even though the former is a weaker acid. Its crystallization gives an aggregated cyclic ion pair, which is composed of two diarylammonium cations, four pentafluorobenzenesulfonate anions, and two oxonium cations. This ion pair is strongly stabilized by four intermolecular and two intramolecular pi-pi attractive interactions and 10 hydrogen bonds. The extremely high catalytic activity of N-(2,6-diphenylphenyl)-N-mesitylammonium pentafluorobenzenesulfonate in the dehydration reactions may be ascribed to the local hydrophobic environment of the tightly aggregated ammonium salts.

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  • The oxorhenium(VII)-catalyzed direct condensation of phosphoric acid with an alcohol Reviewed

    Akira Sakakura, Mikimoto Katsukawa, Kazuaki Ishihara

    ANGEWANDTE CHEMIE-INTERNATIONAL EDITION   46 ( 9 )   1423 - 1426   2007

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  • Direct ester condensation catalyzed by bulky diarylammonium pentafluorobenzenesulfonates Reviewed

    Akira Sakakura, Shoko Nakagawa, Kazuaki Ishihara

    NATURE PROTOCOLS   2 ( 7 )   1746 - 1751   2007

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    A protocol for ester condensation between equimolar amounts of carboxylic acids and alcohols catalyzed by bulky diarylammonium pentafluorobenzenesulfonate is described. We also present procedures for the synthesis of N-(2,6-diisopropylphenyl)-N-mesitylammonium pentafluorobenzenesulfonate. The present ester condensation proceeds well under mild conditions even without the removal of generated water. The synthesis of N-(2,6-diisopropylphenyl)-N-mesitylammonium pentafluorobenzenesulfonate will take similar to 5 days. The ester condensation reactions will take similar to 6 h to 3 days.

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  • Bulky phosphazenium cation catalysis for dehydrative condensation of phosphoric acid with alcohols Reviewed

    Akira Sakakura, Mikimoto Katsukawa, Takaomi Hayashi, Kazuaki Ishihara

    GREEN CHEMISTRY   9 ( 11 )   1166 - 1169   2007

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    A metal-free phosphazenium cation-catalyzed direct dehydrative condensation of phosphoric acid with alcohols has been developed for the environmentally benign synthesis of phosphoric acid monoesters.

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  • Enantioselective Diels-Alder reaction of alpha-acyloxyacroleins catalyzed by chiral 1,1 '-binaphthyl-2,2 '-diammonium salts Reviewed

    Akira Sakakura, Kenji Suzuki, Kazuaki Ishihara

    ADVANCED SYNTHESIS & CATALYSIS   348 ( 16-17 )   2457 - 2465   2006.11

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    A diammonium salt of chiral 1,1'-binaphthyl-2,2'-diamine (2a) and trifluoromethanesulfonimide (Tf2NH) shows excellent catalytic activity and enantioselectivity for the Diels-Alder reaction of alpha-acyl-oxyacroleins. For example, in the presence of 5 mol % of 2a and 9.5 mol % of Tf2NH, the Diels-Alder reaction of alpha-(cyclohexanecarbonyloxy)acrolein with cyclopentadiene proceeded in EtCN at -75 degrees C to give the adducts in 88 % yield with 92 % exo and 91 % ee. The electron-donating property of the acyl group of the alpha-acyloxyacroleins increases the enantioselectivity due to the formation of strong intramolecular hydrogen bonding of the acyl group with a proton of the ammonium group in the transition state. This catalyst can be easily prepared in situ by mixing the commercially available chiral diamine and Tf2NH.

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  • 35 Synthesis of Aurisides A and B, Cytotoxic Macrolide Glycosides of Marine Origin

    Suenaga Kiyotake, Hoshino Hiroshi, Yoshii Takanori, Mori Kazunori, Sone Hiroki, Bessho Yuhki, Sakakura Akira, Hayakawa Ichiro, Yamada Kiyoyuki, Kigoshi Hideo

    Symposium on the Chemistry of Natural Products, symposium papers   ( 48 )   205 - 210   2006.9

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    Aurisides A (1) and B (2) are macrolide glycosides isolated from Japanese sea hare Dolabella auricuralia, which exhibit cytotoxicity against HeLa S_3 cells with IC_<50> values of 0.17 and 1.2μg/mL, respectively. The main structural features of aurisides are a bromine-substituted conjugated diene, a 14-membered lactone, and a cyclic hemiacetal. We achieved the enantioselective synthesis of aurisides A and B by a convergent approach. The C1-C9 segment 4 was prepared from (R)-pantolactone using a reaction of dithiane carbanion with epoxide, stereoselective reduction of β-hydroxyketone with Me_4NBHOAc, and rhodium-catalyzed Reformatsky-type reaction as key steps. The C10-C17 segment 12 was synthesized from (R)-glycidyl trityl ether. The Nozaki-Hiyama-Kishi reaction between 4 and 12 and subsequent reactions including construction of bromine-substituted conjugated diene gave seco acid 10, which was converted into the aglycon (3) of aurisides by construction of the 14-membered lactone. The Mukaiyama glycosylation reaction of the aglycon 3 provided aurisides A (1) and B (2).

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  • 8 Studies on Antitumor Mechanism of Aplyronine A

    Kuroda Takeshi, Suenaga Kiyotake, Handa Tomohisa, Miya Saori, Okamoto Kazuhito, Kanematsu Kengo, Sakakura Akira, Yamada Kiyoyuki, Hirata Kunio, Takata Masaki, Kato Kenichi, Muraoka Shin, Yamamoto Masaki, Tanaka Hiroshi, Kigoshi Hideo

    Symposium on the Chemistry of Natural Products, symposium papers   ( 48 )   43 - 48   2006.9

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    The interaction between actin and aplyronine A, a potent antitumor and actin-depolymerizing substance of marine origin, was investigated by photoaffinity labeling experiments and X-ray structure analysis of actin complex with aplyronine A. Photoaffinity probes consisting of a side-chain portion of aplyronine A as a ligand, a diazirine moiety as a photoaffinity group, and a fluorophor as a detecting group were synthesized. Photolabeling experiments between actin and the probe were carried out. Actin was successfully photolabeled by the fluorescent probe and visualized clearly. The present results provide the first chemical evidence for the direct interaction between actin and the side-chain portion of aplyronine A. X-ray structure analysis of actin-aplyronine A complex was carried out. The analysis showed that Aplyronine A bound to a hydrophobic cleft between subdomains 1 and 3 of actin. The structural feature is that the trimethylserine moiety protrudes toward the bulk solvent region.

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  • Enantioselective synthesis of aurisides A and B, cytotoxic macrolide glycosides of marine origin Reviewed

    Kiyotake Suenaga, Hiroshi Hoshino, Takanori Yoshii, Kazunori Mori, Hiroki Sone, Yuhki Bessho, Akira Sakakura, Ichiro Hayakawa, Kiyoyuki Yamada, Hideo Kigoshi

    TETRAHEDRON   62 ( 33 )   7687 - 7698   2006.8

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    The enantioselective synthesis of aurisides A and B, macrolide glycosides of marine origin, was achieved by a convergent approach. The C1-C9 segment 4 was prepared from (R)-pantolactone, and the C10-C17 segment 14 was synthesized from (R)-glycidyl trityl ether. The Nozaki-Hiyama-Kishi reaction between 4 and 14 and subsequent reactions gave seco acid 10, which was converted into the aglycon (3) of aurisides by construction of the 14-membered lactone and bromine-substituted conjugated diene. The glycosylation reaction of the aglycon provided aurisides A and B. (c) 2006 Elsevier Ltd. All rights reserved.

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  • Synthesis and biological activity of mycalolide analogs Reviewed

    Kiyotake Suenaga, Tomoyuki Kimura, Takeshi Kuroda, Keita Matsui, Saori Miya, Satomi Kuribayashi, Akira Sakakura, Hideo Kigoshi

    TETRAHEDRON   62 ( 35 )   8278 - 8290   2006.8

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    Mycalolide analog 4, consisting only of the side chain of mycalolide B (2), a trisoxazole macrolide of marine origin, was stereoselectively synthesized using Roush crotylboration, an Evans aldol reaction, and a Paterson aldol reaction as key steps. The analog 4 was found to have strong actin-depolymerizing activity. (c) 2006 Elsevier Ltd. All rights reserved.

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  • P-81 ENANTIOSELECTIVE POLYENE HALOCYCLIZATION INDUCED BY NUCLEOPHILIC CHIRAL PHOSPHINES

    Sakakura Akira, Ukai Atsushi, Ishihara Kazuaki

    International Symposium on the Chemistry of Natural Products   2006   "P - 81"   2006.7

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    DOI: 10.24496/intnaturalprod.2006.0__P-81_

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  • Development of environmentally benign catalytic dehydration process Reviewed

    Akira Sakakura, Kazuaki Ishihara

    JOURNAL OF SYNTHETIC ORGANIC CHEMISTRY JAPAN   64 ( 6 )   651 - 663   2006.6

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    More environmentally benign alternatives to current chemical processes, especially large-scale fundamental reactions, are highly desirable for many reactions. We have developed bulky diary-lammonium pentafluorobenzenesulfonates la and 2a as mild and extremely active dehydration catalysts. In the presence of the catalysts, dehydrative cyclization of 1, 3, 5-triketones and ester condensation of carboxylic acids with equimolar amounts of alcohols are performed in heptane by heating at 80 V without the removal of water. We have also developed an efficient molybdenum oxide-catalyzed dehydrative cyclization of serine, threonine, and cysteine derivatives, which gives oxazolines and thiazolies. In the presence of molybdenum oxides, the reaction is carried out by heating at azeotropic reflux with the removal of water. Phosphate monoesters are synthesized from a mixture of phosphoric acid and alcohols in the presence of tributylamine. The reaction is promoted by nucleophilic bases such as N-butylimidazole. The hydroxyl groups of amino alcohols, such as 5'-hydroxyl group of 2, 3'-O-isopropylidene ribonucleosides, are phosphorylated selectively.

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  • Chiral 1,1 '-binaphthyl-2,2 '-diammonium salt catalysts for the enantioselective Diels-Alder reaction with alpha-acyloxyacroleins Reviewed

    Akira Sakakura, Kenji Suzuki, Kazuhiko Nakano, Kazuaki Ishihara

    ORGANIC LETTERS   8 ( 11 )   2229 - 2232   2006.5

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    A diammonium salt of chiral 1,1'-binaphthyl-2,2'-diamine and trifluoromethanesulfonimide (Tf2NH) shows excellent catalytic activity and enantioselectivity for the Diels-Alder reaction of alpha-acyloxyacroleins with cyclic dienes. For example, in the presence of 5 mol % of the ammonium catalyst, the Diels-Alder reaction of alpha-(cyclohexanecarbonyloxy) acrolein with cyclopentadiene proceeded in EtCN at -75 degrees C to give the adducts in 88% yield with 92% exo and 91% ee. This catalyst can be easily prepared in situ by mixing the commercially available chiral diamine and Tf2NH.

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  • Study of the interaction between actin and antitumor substance aplyronine A with a novel fluorescent photoaffinity probe Reviewed

    Takeshi Kuroda, Kiyotake Suenaga, Akira Sakakura, Tomohisa Handa, Kazuhito Okamoto, Hideo Kigoshi

    Bioconjugate Chemistry   17 ( 2 )   524 - 529   2006.3

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    The interaction between actin and aplyronine A, a potent antitumor and actin-depolymerizing substance of marine origin, was investigated by photoaffinity labeling experiments. Photoaffinity probes consisting of a side-chain portion of aplyronine A as a ligand, a diazirine moiety as a photoaffinity group, and a fluorophore as a detecting group were synthesized. Photolabeling experiments between actin and the probe were carried out. Actin was successfully photolabeled by the fluorescent probe and visualized clearly. The present results provide the first chemical evidence for the direct interaction between actin and the side-chain portion of aplyronine A. © 2006 American Chemical Society.

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  • Bulky diarylammonium arenesulfonates as mild and extremely active dehydrative ester condensation catalysts Reviewed

    Akira Sakakura, Shoko Nakagawa, Kazuaki Ishihara

    Tetrahedron   62 ( 2-3 )   422 - 433   2006.1

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    More environmentally benign alternatives to current chemical processes, especially large-scale, fundamental reactions like ester condensations, are highly desirable for many reactions. Bulky diarylammonium pentafluorobenzenesulfonates and tosylates serve as extremely active dehydration catalysts for the ester condensation reaction of carboxylic acids with equimolar amounts of sterically demanding alcohols and acid-sensitive alcohols. Typically, the esterification reaction is performed in heptane by heating at 80°C in the presence of 1 mol% of the catalyst without removing water. Esterification with primary alcohols proceeds without solvents even at room temperature. Furthermore, 4-(N-mesitylamino)polystyrene resin-bound pentafluorobenzenesulfonate can be recycled more than 10 times without a loss of activity. © 2005 Elsevier Ltd. All rights reserved.

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  • P-12 Efficient Synthesis of Oxazolines and Thiazolines Using Molybdenum Oxide-Catalyzed Dehydrative Cyclization Reaction

    Sakakura Akira, Kondo Rei, Umemura Shuhei, Ishihara Kazuaki

    Symposium on the Chemistry of Natural Products, symposium papers   ( 47 )   475 - 480   2005.9

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    Oxazoline, oxazole, thiazoline, and thiazole rings are important constituents of numerous bioactive natural products and pharmaceuticals. The biosynthesis of many naturally occurring oxazolines and thiazolines appears to involve the dehydrative cyclization of serine, threonine, and cysteine residues. Oxazoles and thiazoles are synthesized by the oxidation of oxazolines and thiazolines, respectively. We describe here a biomimetic synthesis of oxazolines and thiazolines catalyzed by molybdenum (IV or VI) oxides, their mode of cyclization is retentive at the β-position. In the course of screening various metal oxides as catalysts for the dehydrative cyclization of dipeptides 1a and 1b, we found that molybdenum oxides had good catalytic activities. Interestingly, the ammonium salts of molybdenum(VI) oxides, (NH_4)_6Mo_7O_<24>・4H_2O and (NH_4)_2MoO_4, exhibited remarkable catalytic activities and gave oxazolines 2a and 2b in a short reaction time, along with small amounts of 3a and 3b. Next, we examined the dehydrative cyclization of cysteine derivatives 4a and 4b to thiazolines 5a and 5b using molybdenum oxides as catalysts. In the case of the dehydrative cyclization of 4a, (NH_4)_6Mo_7O_<24>・4H_2O, (NH_4)_2MoO_4 and MoO_2(acac)_2 showed excellent catalytic activities. MoO_2(acac)_2 could catalyze the dehydrative cyclization of 4b, to give 5b in 70% yield along with 5c (15%). To the best of our knowledge, this is the first example of the catalytic dehydrative cyclization of dipeptide substrates that include serine, threonine, and cysteine residues. A key synthetic intermediate 11 of hennoxazole A and bis(oxazoline)s 13a and 13b were synthesized by the dehydrative cyclization using molybdenum oxide catalysts. In addition, polyaniline-supported MoO_2(acac)_2 could easily be recovered and reused.

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  • Selective synthesis of phosphate monoesters by dehydrative condensation of phosphoric acid and alcohols promoted by nucleophilic bases Reviewed

    Akira Sakakura, Mikimoto Katsukawa, Kazuaki Ishihara

    Organic Letters   7 ( 10 )   1999 - 2002   2005.5

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    (Chemical Equation Presented) Phosphate monoesters are synthesized from a mixture of phosphoric acid (1 or 2 equiv) and alcohols (1 equiv) in the presence of tributylamine. The reaction is promoted by nucleophilic bases such as N-alkylimidazole and 4-(N,N-dialkylamino)pyridine. 2′,3′-I- Isopropylidene ribonucleosides are selectively converted to their 5′-monophosphates without the protection of amino groups in nucleobases. © 2005 American Chemical Society.

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  • Molybdenum oxides as highly effective dehydrative cyclization catalysts for the synthesis of oxazolines and thiazolines Reviewed

    Akira Sakakura, Rei Kondo, Kazuaki Ishihara

    Organic Letters   7 ( 10 )   1971 - 1974   2005.5

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    (Chemical Equation Presented) In the presence of molybdenum oxide the dehydrative cyclization of N-acylserines, N-acylthreonines, and N-acylcysteines can be carried out under Dean-Stark conditions in toluene to give oxazolines and thiazolines. The ammonium salts (NH4)6Mo 7O24·4H2O and (NH4) 2MoO4 have excellent catalytic activities for the dehydrative cyclization of serine and threonine derivatives, and the acetylacetonate complex MoO2(acac)2 has a remarkable catalytic activity for the dehydrative cyclization of cysteine derivatives. In addition, polyaniline-supported MoO2(acac)2 can easily be recovered and reused. © 2005 American Chemical Society.

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  • Bulky diarylammonium arenesulfonates as selective esterification catalysts Reviewed

    Kazuaki Ishihara, Shoko Nakagawa, Akira Sakakura

    Journal of the American Chemical Society   127 ( 12 )   4168 - 4169   2005.3

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    More environmentally benign alternatives to current chemical processes, especially large-scale, fundamental reactions such as ester condensations, are highly desirable for many reactions. Bulky diarylammonium pentafluorobenzenesulfonates and tosylates serve as extremely active dehydration catalysts for the ester condensation reaction of carboxylic acids with equimolar amounts of sterically demanding alcohols and acid-sensitive alcohols. Typically, the esterification reaction is performed in heptane by heating at 80 °C in the presence of 1 mol % of the catalyst without removing water. Esterification with primary alcohols proceeds without solvents even at room temperature. Furthermore, 4-(N-mesitylamino)polystyrene resin-bound pentafluorobenzenesulfonate can be recycled more than 10 times without activity loss. Copyright © 2005 American Chemical Society.

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  • Formal synthesis of optically active ingenol via ring-closing olefin metathesis Reviewed

    Kazushi Watanabe, Yuto Suzuki, Kenta Aoki, Akira Sakakura, Kiyotake Suenaga, Hideo Kigoshi

    Journal of Organic Chemistry   69 ( 23 )   7802 - 7808   2004.11

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    The construction of strained carbon skeletons by ring-closing olefin metathesis (RCM) was investigated. With well-designed diene 4, RCM was found to be applicable to the formation of a highly strained inside-outside bicyclo[4.4.1]undecane skeleton of ingenol, a bioactive diterpenoid, and formal total synthesis of optically active ingenol (1) was achieved. The key features of this synthesis are construction of an A-ring by spirocyclization of the ketone with an allylic chloride unit, 26, and ring closure of a B-ring by olefin metathesis. Starting from Funk's keto ester 6, the key intermediate aldehyde 9 in Winkler's total synthesis was synthesized in eight steps in 12.5% overall yield. This strategy of direct cyclization of a strained inside-outside skeleton provided the first easy access to optically active ingenol.

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  • Spongiacysteine, a novel cysteine derivative from marine sponge Spongia sp. Reviewed

    Keiko Kobayashi, Hiroki Shimogawa, Akira Sakakura, Toshiaki Teruya, Kiyotake Suenaga, Hideo Kigoshi

    Chemistry Letters   33 ( 10 )   1262 - 1263   2004.10

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    A novel cysteine derivative, spongiacysteine (1), was isolated from marine sponge Spongia sp. The gross structure was elucidated by detailed spectroscopic analysis, and the absolute stereostructure was established by its total synthesis. This compound showed moderate antimicrobial activity against rice blast fungus Pyricularia oryzae.

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  • 99(P-32) Formal Synthesis of Optically Active Ingenol

    Watanabe Kazushi, Suzuki Yuto, Aoki Kenta, Sakakura Akira, Suenaga Kiyotake, Kigoshi Hideo

    Symposium on the Chemistry of Natural Products, symposium papers   ( 46 )   569 - 574   2004.10

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    Ingenol is a diterpenoid isolated from Euphorbia ingens, possessing a bicyclo[4.4.1]undecane skeleton with a highly strained inside, outside-intrabridgehead stereochemistry. Several strategies for construction of the unique skeleton have been reported, however, direct cyclization to the inside, ousidet-bicyclo[4.4.1]undecane system has not been reported. Recently, two total syntheses in a racemic form using the aforementioned strategies were reported by Winkler and Tanino-Kuwajima. We would like to report the construction of strained carbon skeletons of ingenol by direct cyclization with ring-closing olefin metathesis (RCM). With well-designed diene compounds 4, 23, and 24, RCM was found to be applicable to the formation of a highly strained skeleton of ingenol, and formal total synthesis of optically active ingenol (1) was achieved. The key features of this synthesis are construction of an A-ring by spirocyclization of ketone 21 with an allylic chloride unit and ring closure of a B-ring by olefin metathesis. Starting from Funk's keto ester 17, the key intermediate aldehyde 27 in Winkler's total synthesis was synthesized in eight steps in 12.5% overall yield. This strategy of direct cyclization of a strained inside-outside skeleton provided the first easy access to optically active ingenol.

    DOI: 10.24496/tennenyuki.46.0_569

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  • 58(P-35) Synthesis and Biological Activities of Aplyronine A and the Related Compounds

    Suenaga K., K. Takeshi, Handa T., Miya S., K. Kengo, Sakakura A., Yamada K., K. Hideo, Hirata K., Takata M., Kato K., Muraoka S., Yamamoto M., Tanaka H.

    Symposium on the Chemistry of Natural Products, symposium papers   ( 46 )   323 - 328   2004.10

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    Aplyronine A (1) is a potent antitumor macrolide isolated from the sea hare Aplysia kurodai, and mycalolide B (2) is a cytotoxic and antifungal macrolide isolated from a sponge of the genus Mycale. These macrolides interact with actin, one of the major proteins in cytoskeleton. We achieved total synthesis of aplyronine A (1) and its analogs and investigated the structure-activity relationships. We improved the synthesis of the side chain portion of aplyronine A (1) by using the Paterson aldol reaction and subsequent stereoselective reduction with Me_4NBH(OAc)_3 as key steps. The synthetic analogs 3 and 4 that only consists of the side chain part of aplyronine A (1) and mycalolide B (2) turned out to exhibit a strong actin depolymerizing activity, considering the size of the molecule. This result revealed that the side chain portion in aplyronine A (1) and mycalolide B (2) was responsible for the potent activity of 1 and 2. Analysis of the interaction of aplyronine analogs, such as 30 and 31, with actin by a photoaffinity labeling method has been carried out. Crystallization and X-ray structure analysis of actin complex with aplyronine A (1) also are in progress.

    DOI: 10.24496/tennenyuki.46.0_323

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  • Jolkinolide D pharmacophore: Synthesis and reaction with biomolecules Reviewed

    Akira Sakakura, Yui Takayanagi, Hiroki Shimogawa, Hideo Kigoshi

    Tetrahedron   60 ( 33 )   7067 - 7075   2004.8

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    To obtain information on the chemical modification of biomolecules with jolkinolide D, a bioactive diterpenoid of plant origin, jolkinolide D pharmacophore was synthesized, and its reactivity toward amino acids, nucleosides, and DNA was investigated. © 2004 Elsevier Ltd. All rights reserved.

    DOI: 10.1016/j.tet.2003.08.080

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  • Synthesis and actin-depolymerizing activity of mycalolide analogs Reviewed

    Kiyotake Suenaga, Saori Miya, Takeshi Kuroda, Tomohisa Handa, Kengo Kanematsu, Akira Sakakura, Hideo Kigoshi

    Tetrahedron Letters   45 ( 28 )   5383 - 5386   2004.7

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    Mycalolide analog 4, consisting only of the side chain of mycalolide B (2), was stereoselectively synthesized and was found to have strong actin-depolymerizing activity. © 2004 Elsevier Ltd. All rights reserved.

    DOI: 10.1016/j.tetlet.2004.05.078

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  • Nonspecificity Induces Chiral Specificity in the Folding Transition of Giant DNA Reviewed

    Michiko Ito, Akira Sakakura, Naomi Miyazawa, Shizuaki Murata, Kenichi Yoshikawa

    Journal of the American Chemical Society   125 ( 42 )   12714 - 12715   2003.10

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    The all-or-none type DNA folding transition from a coil to globule can be differentiated by the chirality of the triamines. The fluorescent microscope observation on single DNA molecules makes it clear that the tripeptides obtained from naturally occurring basic amino acids (L-lysine or L-arginine) can compact DNA molecules at concentrations lower than those from D-isomers. Nanometer-sized beads are found in the AFM images on the folded DNA molecule. Copyright © 2003 American Chemical Society.

    DOI: 10.1021/ja036745x

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  • 106(P-60) Jolkinolide D Pharmacophore : Synthesis and Reaction with Amino Acids, Nucleosides, and DNA

    Sakakura Akira, Takayanagi Yui, Shimogawa Hiroki, Kigoshi Hideo

    Symposium on the Chemistry of Natural Products, symposium papers   ( 44 )   623 - 628   2002.9

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    Jolkinolide D (1) is a diterpenoid isolated from Euphorbia jolkini Boiss in 1974, and its stereostructure was recently determined by X-ray crystallographic analysis. It inhibited tumor invasion into the basement membrane and induced apoptosis in tumor cells. Jolkinolide D (1) has a γ,δ-unsaturated-β-hydroxy-α-methylene lactone unit as the pharmacophore structure, which suggests that jolkinolide D (1) might alkylate biomolecules such as proteins and DNA irreversibly. Since there are no other compounds that have the pharmacophore, reactivities of the unit toward nucleophiles have not hitherto been investigated. For the purpose of obtaining preliminary information on the chemical modification of biomolecules with jolkinolide D (1), jolkinolide D pharmacophore (2) was synthesized from 6-(tert-butyldimethylsilyloxy)-3-methyl-2-cyclohexenone (3) and 2-iodoallylalcohol (4), and its reactivity toward amino acids, nucleosides, and DNA was investigated. It was found that the order of reactivity of jolkinolide D pharmacophore (2) toward the nucleophiles in the amino acids at pH 7.5 is the thiol group in L-cysteine and glutathione > the imidazolyl group in L-histidine, the α-amino groups in amino acids > the carboxyl groups in amino acids. Jolkinolide D pharmacophore (2) alkylated 2'-deoxyguanosine at the N-1 position (pH 7.5) and thymidine at the N-3 position (pH 8.7), and modified DNA at the same sites in lower yields.

    DOI: 10.24496/tennenyuki.44.0_623

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  • Jolkinolide D pharmacophore: Synthesis and reaction with amino acids, nucleosides, and DNA Reviewed

    Akira Sakakura, Yui Takayanagi, Hideo Kigoshi

    Tetrahedron Letters   43 ( 34 )   6055 - 6058   2002.8

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    For the purpose of obtaining preliminary information on the chemical modification of biomolecules with jolkinolide D, a bioactive diterpenoid of plant origin, jolkinolide D pharmacophore, was synthesized and its reactivity toward amino acids, nucleosides, and DNA was investigated. © 2002 Published by Elsevier Science Ltd.

    DOI: 10.1016/S0040-4039(02)01195-4

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  • Effect of molecular sieves in the liquid-phase synthesis of nucleotides via the phosphoramidite method Reviewed

    Yoshihiro Hayakawa, Akiyoshi Hirata, Jun-Ichiro Sugimoto, Rie Kawai, Akira Sakakura, Masanori Kataoka

    Tetrahedron   57 ( 42 )   8823 - 8826   2001.10

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    It is demonstrated that the reaction of a nucleoside phosphoramidite and a nucleoside aided by a suitable promoter in the presence of molecular sieves 3A or 4A in a liquid phase is efficiently performed by the use of stoichiometric amounts of the reactants to give the desired coupling product in an excellent yield. © 2001 Elsevier Science Ltd. All rights reserved.

    DOI: 10.1016/S0040-4020(01)00880-8

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  • A facile synthesis of 5′-end solid-anchored, 3′-end free oligodeoxyribonucleotides via the (5′→3′)-elongated phosphoramidite strategy Reviewed

    Akira Sakakura, Yoshihiro Hayakawa

    Nucleosides, Nucleotides and Nucleic Acids   20 ( 3 )   213 - 227   2001

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    It is demonstrated that not only N2- but also O 6-protection of the guanine base is necessary for obtaining the oligodeoxyribonucleotides in high yields and at a high purity in the solid-phase synthesis via the (5′ → 3′)-chain elongated phosphoramidite approach.

    DOI: 10.1081/NCN-100002082

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  • Acid/azole complexes as highly effective promoters in the synthesis of DNA and RNA oligomers via the phosphoramidite method Reviewed

    Y. Hayakawa, R. Kawai, A. Hirata, J. I. Sugimoto, M. Kataoka, A. Sakakura, M. Hirose, R. Noyori

    Journal of the American Chemical Society   123 ( 34 )   8165 - 8176   2001

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    The utility of various kinds of acid salts of azole derivatives as promoters for the condensation of a nucleoside phosphoramidite and a nucleoside is investigated. Among the salts, N-(phenyl)imidazolium triflate, N-(p-acetylphenyl)imidazolium triflate, N-(methyl)benzimidazolium triflate, benzimidazolium triflate, and N-(phenyl)imidazolium perchlorate have shown extremely high reactivity in a liquid phase. These reagents serve as powerful activators of deoxyribonucleoside 3′-(allyl N,N-diisopropylphosphoramidite)s or 3′-(2-cyanoethyl N,N-diisopropylphosphoramidite)s employed in the preparation of deoxyribonucleotides, and 3′-O-(tert-butyldimethylsilyl)ribonucleoside 2′-(N,N-diisopropylphosphoramidite)s or 2′-O-(tert-butyldimethylsilyl)-ribonucleoside 3′-(N,N-diisopropylphosphoramidite)s used for the formation of 2′-5′ and 3′-5′ internucleotide linkages between ribonucleosides, respectively. The azolium salt has allowed smooth and high-yield condensation of the nucleoside phosphoramidite and a 5′-O-free nucleoside, in which equimolar amounts of the reactants and the promoter are employed in the presence of powdery molecular sieves 3A in acetonitrile. It has been shown that some azolium salts serve as excellent promoters in the solid-phase synthesis of oligodeoxyribonucleotides and oligoribonucleotides. For example, benzimidazolium triflate and N-(phenyl)imidazolium triflate can be used as effective promoters in the synthesis of an oligodeoxyribonucleotide, 5′CGACACCCAATTCTGAAAAT3′ (20mer), via a method using O-allyl/N-allyloxycarbonyl-protected deoxyribonucleoside 3′-phosphoramidites or O-(2-cyanoethyl)/N-phenoxyacetyl-protected deoxyribonucleotide 3′-phosphoramidite as building blocks, respectively, on high-cross-linked polystyrene resins. Further, N-(phenyl)imidazolium triflate is useful for the solid-phase synthesis of oligoribonucleotides, such as 5′AGCUACGUGACUACUACUUU3′ (20mer), according to an allyl/allyloxycarbonyl-protected strategy. The utility of the azolium promoter has been also demonstrated in the liquid-phase synthesis of some biologically important substances, such as cytidine-5′-monophosphono-N-acetylneuraminic acid (CMP-Neu5Ac) and adenylyl(2′-5′)adenylyl(2′-5′)adenosine (2-5A core).

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  • A novel synthesis of oligonucleotide-peptide conjugates with a base- labile phosphate linker between the two components according to the allyl- protected phosphoramidite strategy Reviewed

    Akira Sakakura, Yoshihiro Hayakawa

    Tetrahedron   56 ( 26 )   4427 - 4435   2000.6

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    An efficient synthesis of base-labile nucleotide-peptide conjugates has been accomplished, in which the two components are directly linked between the terminal hydroxyl of a nucleotide and the hydroxyl of a serine or threonine residue of a peptide by a phosphodiester bond. This synthesis utilizes the phosphoramidite method with allyl for the phosphate linkages and the C-terminal of the peptide and allyloxycarbonyl for the nucleoside bases and the N-terminal of the peptide. In this synthesis, the removal of the allylic protecting groups and the detachment of the products was achieved under non-basic or mild basic conditions to bring about no conspicuous decomposition of the labile phosphate linker, and thus the target conjugates were obtained at a high purity and in high yields. (C) 2000 Elsevier Science Ltd.

    DOI: 10.1016/S0040-4020(00)00376-8

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  • A novel approach to oligodeoxyribonucleotides bearing phosphoric acid esters at the 3'-terminals via the phosphoramidite method with allyl protection: An efficient synthesis of base-labile nucleotide-amino acid and - peptide conjugates Reviewed

    Akira Sakakura, Yoshihiro Hayakawa, Hitoshi Harada, Masaaki Hirose, Ryoji Noyori

    Tetrahedron Letters   40 ( 23 )   4359 - 4362   1999.6

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    A new method for synthesis of 3'-end-phosphorylated DNA oligomers via the phosphoramidite method with allyl protection has been developed. This method is particularly useful for the preparation of derivatives with base- labile structures such as oligoDNA-OPO(OH)OCH2CH(R)Z, in which Z is an electron-withdrawing function. For example, a oligonucleotide-amino acid conjugate, 5'TGTCGACACCCAATT3'-OPO(OH)OCH2CH(NH2)COOH, and a oligonucleotide-peptide conjugate, 5'TGTCGACACCCAATT3'- OPO(OH)OCH2CH(NH2)CONHCH2COOH, have been obtained in high purity.

    DOI: 10.1016/S0040-4039(99)00748-0

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  • Aplyronine A, a potent antitumor substance of marine origin, aplyronines B and C, and artificial analogues: Total synthesis and structure-cytotoxicity relationships Reviewed

    Hideo Kigoshi, Kiyotake Suenaga, Tsuyoshi Mutou, Takeshi Ishigaki, Toshiyuki Atsumi, Hiroyuki Ishiwata, Akira Sakakura, Takeshi Ogawa, Makoto Ojika, Kiyoyuki Yamada

    Journal of Organic Chemistry   61 ( 16 )   5326 - 5351   1996.8

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    The enantioselective total synthesis of aplyronine A (1), a potent antitumor substance of marine origin, was achieved by a convergent approach. Three segments 4, 5, and 6, corresponding to the C5-C11, C21-C27, and C28-C34 portions of aplyronine A (1), were prepared using the Evans aldol reaction and the Sharpless epoxidation as key steps. The coupling reaction of 4 with iodide 7 followed by Julia olefination with sulfone 8 gave the C5-C20 segment 9, while the Julia coupling reaction between segments 5 and 6 provided the C21-C34 segment 10. Julia olefination between segments 9 and 10 and the subsequent four-carbon homologation reaction led to seco acid 83, which was converted into aplyronine A (1) by Yamaguchi lactonization followed by the introduction of two amino acids. The use of the [(3,4-dimethoxybenzyl)oxy]methyl group as a protecting group for the hydroxyl at C29 was crucial for this synthesis. The enantioselective synthesis of two natural congeners, aplyronines B (2) and C (3), was also carried out using the intermediates for the synthesis of 1, which determined the absolute stereostructures of 2 and 3 unambiguously. To study the structure-cytotoxicity relationships of aplyronines, artificial analogues of 1 were synthesized and their cytotoxicities were evaluated: the trimethylserine moiety, two hydroxyl groups, and the side chain portion in 1 turned out to be important in the potent cytotoxicity shown by 1. Biological studies with aplyronine A (1) showed that 1 inhibited polymerization of G-actin to F-actin and depolymerized F-actin to G-actin.

    DOI: 10.1021/jo9606113

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  • Absolute stereochemistry and synthesis of aplyronines B and C, the congeners of aplyronine A, a potent antitumor substance of marine origin Reviewed

    Kiyotake Suenaga, Takeshi Ishigaki, Akira Sakakura, Hideo Kigoshi, Kiyoyuki Yamada

    Tetrahedron Letters   36 ( 28 )   5053 - 5056   1995.7

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    Synthesis of aplyronines B and C, the congeners of aplyronine A, was achieved enantioselectively, which established their stereostructures. © 1995.

    DOI: 10.1016/0040-4039(95)00921-X

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  • Total synthesis of aplyronine A, a potent antitumor substance of marine origin Reviewed

    Kigoshi Hideo, Ojika Makoto, Ishigaki Takeshi, Suenaga Kiyotake, Mutou Tsuyoshi, Sakakura Akira, Ogawa Takeshi, Yamada Kiyoyuki

    Journal of the American Chemical Society   116 ( 16 )   7443 - 7444   1994.8

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  • Synthetic Studies on Aplyronine A, a Potent Antitumor Substance of Marine Origin: Stereocontrolled Synthesis of the C21-C34 Segment Reviewed

    Hideo Kigoshi, Makoto Ojika, Kiyotake Suenaga, Tsuyoshi Mutou, Junko Hirano, Akira Sakakura, Takeshi Ogawa, Masanori Nisiwaki, Kiyoyuki Yamada

    Tetrahedron Letters   35 ( 8 )   1247 - 1250   1994.2

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    The C21-C34 segment 2 of aplyronine A (1), a potent antitumor substance of marine origin, was synthesized enantioselectively in 25 steps (17% overall yield) from imide 11. © 1994.

    DOI: 10.1016/0040-4039(94)88035-2

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  • 23 STEREOCHEMISTRY AND SYNTHETIC STUDY OF APLYRONINE A, AN ANTITUMOR MACROLIDE OF MARINE ORIGIN

    Kigoshi H., Ojika M., Ishigaki T., Suenaga K., Muto T., Sakakura A., Ogawa T., Nisiwaki M., Tsukada I., Yamada K.

    Symposium on the Chemistry of Natural Products, symposium papers   ( 35 )   174 - 178   1993.9

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    Aplyronine A (1) is a potent antitumor macrolide isolated as a minute component from the sea hare Aplysia kurodai. The gross structure of 1 was determined by the spectral analysis and chemical degradation. We report herein the absolute stereostructure of 1 and the result of the synthetic study. Chemical degradation of 1 afforded five fragments 2-6. Enantioselective syntheses of the fragments 4a and 5a were performed to disclose the absolute stereochemistry of seven chiral centers (C7-C10, C13, C17, and C19). HPLC analyses of the fragments 2 and 3 using chiral columns disclosed that N,N,O-trimethylserine and N,N-dimethylalanine moieties of 1 were scalemic mixtures (S:R=52:48 for 2; 72:28 for 3). On the basis of the result of the previous and present studies, the absolute stereostructure of aplyronine A (1) was elucidated unambiguously. The synthetic study of 1 was carried out using the Evans aldol reaction and the Sharpless epoxidation reaction as key steps. Starting from N-propionylurethane 11, the C5-C20 segment 13 and the C21-C34 segment 16 were synthesized. The Julia coupling reaction of 13 with 16 followed by four-carbons homologation and lactonization provided 24-membered lactone 17.

    DOI: 10.24496/tennenyuki.35.0_174

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MISC

  • Copper(II) Triflimide

    Akira Sakakura, Kazuaki Ishihara

    April 2017   1 - 4   2017

  • Hetero-Diels-Alder Reactions

    K. Ishihara, A. Sakakura

    Comprehensive Organic Synthesis: Second Edition   5   409 - 465   2014.2

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    Diels-Alder reactions that include a heteroatom in the dienes or dienophiles are called 'hetero-Diels-Alder reactions.' Hetero-Diels-Alder reactions are highly useful for the stereoselective construction of a variety of heterocycles, and have been extensively used in the syntheses of bioactive natural and synthetic compounds. Over the past 20 years, various diastereo- and enantioselective hetero-Diels-Alder reactions have been developed. This chapter describes recent significant advancements in this field since the publication of the first edition of Comprehensive of Organic Synthesis in 1991. First, we summarize enantioselective hetero-Diels-Alder reactions of carbonyl compounds, which are promoted by chiral Lewis acid catalysts or organocatalysts. Next, we describe representative examples of asymmetric aza-Diels-Alder reactions. We also summarize recent significant advances in the stereoselective hetero-Diels-Alder reactions of other dienes and dienophiles such as nitroso compounds. Finally, we present representative studies on the biomimetic synthesis of bioactive natural products using hetero-Diels-Alder reactions. © 2014 Elsevier Ltd. All rights reserved.

    DOI: 10.1016/B978-0-08-097742-3.00510-3

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  • Intermolecular Diels-Alder Reactions

    K. Ishihara, A. Sakakura

    Comprehensive Organic Synthesis: Second Edition   5   351 - 408   2014.2

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    The Diels-Alder reaction is one of the most powerful carbon-carbon bond-forming reactions and is a versatile tool for the synthesis of many bioactive natural products. Since it was first shown that the Diels-Alder reaction could be effectively promoted by Lewis acids, stereoselective versions have been extensively investigated. This chapter focuses on representative achievements in this field after publication of the first edition of Comprehensive of Organic Synthesis in 1991. The authors summarize chiral Lewis acid catalysis, including chiral boron(III), copper(II), and other metal complexes, for use in diastereo- and enantioselective Diels-Alder reactions. Next, recent significant advances in asymmetric organocatalysis, including organoammonium catalysis and hydrogen-bonding catalysis, are described. Examples of natural product syntheses based on the asymmetric Diels-Alder reaction using Lewis acid catalysts or organocatalysts are also described. Finally, representative studies on the biomimetic synthesis of natural compounds using intermolecular Diels-Alder reactions are shown. © 2014 Elsevier Ltd. All rights reserved.

    DOI: 10.1016/B978-0-08-097742-3.00509-7

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  • 6.10 C-C Bond Formation: Diels-Alder Reaction

    K. Ishihara, A. Sakakura

    Comprehensive Chirality   6   264 - 292   2012.9

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    The asymmetric Diels-Alder reaction is one of the most powerful organic transformations and is a versatile tool for the synthesis of many bioactive natural products. The asymmetric hetero-Diels-Alder reactions of carbonyl compounds and imino compounds are also among the most powerful methodologies for the construction of optically active heterocycles, and there are extensive applications of these reactions in the synthesis of bioactive natural and unnatural compounds. In addition to conventional Lewis acid catalysis, organocatalysis has been successfully applied to the enantioselective Diels-Alder reaction. Through the use of chiral secondary and primary organoammonium salt catalysts and hydrogen-bonding catalysts, the enantioselective Diels-Alder reaction of dienes with α,. β-unsaturated carbonyl compounds can be promoted. Chiral secondary and primary organoammonium salt catalysts activate α,. β-unsaturated carbonyl compounds via the formation of an iminium cation intermediate, whereas chiral hydrogen-bonding catalysts activate these compounds via coordination of the carbonyl group. © 2012 Elsevier Ltd. All rights reserved.

    DOI: 10.1016/B978-0-08-095167-6.00610-8

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  • [4+2]-Cycloaddition Reactions

    Akira Sakakura, Kazuaki Ishihara

    Science of Synthesis, Stereoselective Synthesis 3: Stereoselective Pericyclic Reactions, Cross Coupling, and C–H and C–X Activation   67 - 123   2011

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  • A facile solid-phase synthesis of oligodeoxyribo-nucleotides and their amino acid conjugates via the allyl-protected phosphoramidite approach with benzimidazolium triflate as a promoter

    Y Hayakawa, A Sakakura, SB Heidenhain, M Kataoka

    CHEMISTRY OF NUCLEIC ACID COMPONENTS   2   105 - 108   1999

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    Utility of benzimidazolium triflate as a promoter in the solid-phase synthesis of oligodeoxyribonucleotides and their amino acid conjugates via the phosphoramidite method with allyl protection has been demonstrated.

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Presentations

  • Development of convergent synthetic method toward natural products with bicyclo[3.2.1]octane core

    Naochika Matsumaru, Haruki Mizoguchi, Akira Sakakura

    2023.3.25 

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    Event date: 2023.3.22 - 2023.3.25

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  • Toward the biomimetic synthesis of grayanane diterpenoids

    Hidetoshi Kamada, Haruki Mizoguchi, Akira Sakakura

    2023.3.25 

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  • Asymmetric Direct Mannich Reaction of α-Ketoesters Catalyzed by Sulfonamide-substituted Chiral Lewis Acid Catalyst

    Takeru Abe, Haruki Mizoguchi, Akira Sakakura

    2023.3.24 

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  • Towards the diversity-oriented synthesis of indole diterpenes

    2020.9.23 

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    Event date: 2020.9.22 - 2020.9.24

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  • ジアステレオ選択的Henry反応を鍵とするマンザシジンBの形式全合成

    荒木雄也, 三好夏美, 森本一樹, 溝口玄樹, 坂倉彰

    第61回天然有機化合物討論会  2019.9.11 

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  • ゲラニル誘導体のバイオミメティックなブロモ環化反応に有効なチオウレア触媒

    坂倉彰, 寺崎美幸, 塩本啓一, 溝口玄樹

    第60回天然有機化合物討論会  2018.9.27 

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  • Development of a conjunctive cross-coupling of vinylboronic ester ate-complex with ketene

    2022.3.26 

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  • Synthesis of polycyclic skeletons including bicyclo[3.2.1]octane ring

    2022.3.26 

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  • Construction of seven-membered carbocycles using 1,2-metallate rearrangement of cyclopropenylboronic ester ate-complex

    2022.3.24 

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  • Asymmetric synthesis of b-hydroxy quaternary amino acids via chiral Lewis acid-catalyzed direct aldol reaction

    2022.3.24 

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  • Mechanistic investigation and substrate scope evaluation of an aryne-triggered 1,2-metallate rearrangement of vinylboronic esters

    2021.3.19 

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  • Stereoselective Construction of Contiguous Asymmetric Quaternary Carbon Centers of Indole Terpenes

    2021.3.19 

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  • Development of an intramolecular C‒H silylmethylation of benzyl alcohol derivatives utilizing photoexcited palladium complex

    2021.3.19 

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  • Design of Chiral Lewis Acid Catalyst for the Asymmetric Direct Mannich Reaction of α-Ketoesters

    2021.3.19 

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  • Enantioselective Diels-Alder Reaction of 3-Nitrocoumarins Promoted by Chiral organoammonium Salt Catalysts

    2021.3.19 

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  • Synthesis of highly substituted boronic ester utilized aryne-triggered 1,2-metallate rearrangement of vinylboronic ester

    2021.3.19 

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  • Synthetic Study of Terpendole E: Stereoselective Construction of Contiguous Asymmetric Quaternary Carbon Centers

    2020.3.25 

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  • Expeditious Construction of Highly Oxygenated Terpenoid Skeletons Utilizing Desymmetrizing Reductive-Heck Cyclization

    2020.3.23 

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  • Investigation of Stereoselective Construction of α,α-Disubstituted β-Hydroxy-α-Amino Acid Structure Using Chiral Lewis Acid Catalysts

    2020.3.23 

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  • Synthesis and Biological Evaluation of Coprinoferrin

    2020.3.22 

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  • Stereoselective construction of highly substituted cyclopropylboronic esters enabled by 1,2-metallate rearrangement of boron-ate complex

    2020.3.22 

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  • Development of a Conjunctive-cross Coupling of Alkenylboronic Ester Ate-complex Enabled by an Aryne Triggered Strain-release 1,2-Metallate Rearrangement

    2020.3.22 

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  • アルテミシジン類のシクロペンタン部の立体選択的合成研究

    早川一郎, 永易杏菜, 坂倉彰

    第116回有機合成シンポジウム2019【秋】  2019.11.1 

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  • Synthetic Study of Yuzurimine-Type Alkaloids: Stereoselective Construction of Heterocyclic Portion

    2019.3.17 

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  • Enantioselective 1,3-Dipolar Cycloaddition of α-Substituted acroleins with Nitrones Catalyzed by Chiral Organoammonium salts

    2019.3.17 

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  • Investigation of Asymmetric Direct Mannich Reaction of α-Ketoesters Promoted by Chiral Lewis Acid Catalyst

    2019.3.17 

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  • Synthetic study of manzacidins A, B and C based on diastereoselective Henry reaction

    2019.3.17 

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  • Synthetic Studies of Altemicidin-type Alkaloids: Stereoselective Construction of Cyclopentane Portion

    2019.3.17 

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  • キラルなブレンステッド酸触媒を用いた3-ニトロクマリンの不斉Diels–Alder反応と速度論的光学分割

    坂倉彰, 藤井裕大, 中尾亮太, 早川一郎, 溝口玄樹

    第11回有機触媒シンポジウム  2018.12.3 

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Industrial property rights

  • γ-チューブリン阻害剤

    臼井健郎, 早川一郎, 畑中大成, 坂倉 彰

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    Application no:特願2018-143346  Date applied:2018.7.31

    Announcement no:特開2020- 019732  Date announced:2020.2.6

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  • ピロリン酸エステル化合物、ビスリン酸エステル化合物及び触媒

    石原一彰, 坂倉 彰

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    Application no:特願2012-160092  Date applied:2012.7.19

    Patent/Registration no:特許第6168665号  Date registered:2017.7.7  Date issued:2017.7.26

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  • 新規なジヒドロピラン化合物及びその製法

    石原一彰, 坂倉 彰

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    Application no:特願2012-032401  Date applied:2012.2.17

    Announcement no:特開2013-166736  Date announced:2013.8.29

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  • α-ヒドロキシカルボン酸アミド化合物の製法及び新規なアリールボロン酸化合物

    石原一彰, 坂倉 彰

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    Application no:特願2012-032400  Date applied:2012.2.17

    Patent/Registration no:特許第5881189号  Date registered:2016.2.12  Date issued:2016.3.9

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  • エステルの加水分解によるカルボン酸及びアルコールの製造方法

    石原一彰, 坂倉 彰, 越仮良樹

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    Application no:特願2011-289040  Date applied:2011.12.28

    Patent/Registration no:特許第6061399号  Date registered:2016.12.22  Date issued:2017.1.18

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  • カルボン酸無水物の製造方法及びアリールボロン酸化合物

    石原一彰, 坂倉 彰

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    Application no:特願2009-058720  Date applied:2009.3.11

    Patent/Registration no:特許第5747330号  Date registered:2015.5.22  Date issued:2015.7.15

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  • 水中での脱水縮合によるエステル製造方法

    石原一彰, 坂倉 彰

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    Application no:特願2009-058719  Date applied:2009.3.11

    Announcement no:特開2010-209027  Date announced:2010.9.24

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  • エステルの製造法

    石原一彰, 坂倉 彰, 木幡康則

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    Application no:特願2007-213235  Date applied:2007.8.20

    Announcement no:特開2009-046415  Date announced:2009.3.5

    Patent/Registration no:特許第5419119号  Date registered:2013.11.29  Date issued:2014.2.19

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  • リン酸エステルの製造方法

    石原一彰, 坂倉 彰, 勝川幹基, 井上佳尚

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    Application no:特願2007-42875  Date applied:2007.2.22

    Announcement no:特開2008-201764  Date announced:2008.9.4

    Patent/Registration no:特許第5067752号  Date registered:2012.8.24  Date issued:2012.11.7

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  • リン酸モノエステル製造用触媒及びリン酸モノエステルの製造方法

    石原一彰, 坂倉 彰

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    Application no:PCT/JP2006/324852  Date applied:2006.12.13

    Announcement no:WO2007/097100  Date announced:2007.8.30

    Patent/Registration no:特許第4210764号  Date registered:2008.11.7  Date issued:2009.1.21

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  • チアゾリン製造用触媒、チアゾリン化合物の製法、オキサゾリン製造用触媒及びオキサゾリン化合物の製法

    石原一彰, 坂倉 彰

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    Application no:特願2006-050064  Date applied:2006.2.27

    Announcement no:特開2007-222851  Date announced:2007.9.6

    Patent/Registration no:特許第4178251号  Date registered:2008.9.5  Date issued:2008.11.12

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  • ディールス・アルダー反応触媒および不斉環化付加生成物の製造方法

    石原一彰, 坂倉 彰

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    Application no:特願2006–050063  Date applied:2006.2.27

    Announcement no:特開2007-222850  Date announced:2007.9.6

    Patent/Registration no:特許第4189500号  Date registered:2008.9.26  Date issued:2008.12.3

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  • エステル製造方法及びエステル化触媒

    石原一彰, 坂倉 彰

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    Application no:PCT/JP2005/004398  Date applied:2005.3.8

    Announcement no:WO2005/085172  Date announced:2005.9.15

    Patent/Registration no:特許第4734607号  Date registered:2011.5.13  Date issued:2011.7.27

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  • オキサゾリン化合物の製法及びチアゾリン化合物の製法

    石原一彰, 坂倉 彰

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    Application no:特願2004-141263  Date applied:2004.5.11

    Announcement no:特開2005-320304  Date announced:2005.11.17

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Awards

  • Asian Core Program Lectureship Award

    2010.11  

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  • Banyu Chemist Award

    2009.12  

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    Country:Japan

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  • 有機合成化学奨励賞

    2008.2  

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    Country:Japan

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  • 日本化学会第86春季年会 若い世代の特別講演賞

    2006.3  

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  • 萬有製薬研究企画賞

    2006.2   有機合成化学協会  

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  • Thieme Chemistry Journal Award

    2006  

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    Country:Japan

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  • 有機合成化学協会東海支部奨励賞

    2005.7  

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Research Projects

  • Development of Methods for Synthesis of Aminosugars by Catalytic Asymmetric Addition Reactions of alpha-Ketoesters

    Grant number:18K05123  2018.04 - 2021.03

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

    Sakakura Akira

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    Grant amount:\4420000 ( Direct expense: \3400000 、 Indirect expense:\1020000 )

    Amino sugars, which are useful antibiotics, have carbon skeleton bearing several hydroxy and amino groups. Since the structures of amino sugars are highly complex, the stereoselective synthesis of amino sugars is quite difficult. In this study, we have developed the methods of stereoselective synthesis of amino sugars by using asymmetric catalyst. As results, we succeeded to develop several enantioselective carbon-carbon bond forming reaction. In addition, we achieved formal total synthesis of manzacidin B, which have carbon skeleton bearing continuous amino and hydroxy groups.

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  • 分子内n-カチオン相互作用を利用した有機分子ルイス酸触媒の精密設計

    Grant number:26105739  2014.04 - 2016.03

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

    坂倉 彰

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    Grant amount:\7020000 ( Direct expense: \5400000 、 Indirect expense:\1620000 )

    1.カチオン性キラルホウ酸エステル触媒の精密設計
    我々はこれまでに,配位子のルイス塩基性部位と金属カチオンとの相互作用(n-カチオン相互作用)を鍵とする分子設計により,優れた基質一般性を示すキラル金属ルイス酸触媒の開発に成功している。この研究を基に,これまであまり研究が進んでいないカチオン性ルイス酸性有機分子触媒の精密設計を行った。分子内のルイス塩基性部位による相互作用によってカチオン性をもたせつつ安定性を確保する触媒設計である。N-アルキルアミノアルコールとホウ酸トリメチルからカチオンホウ酸エステル触媒を調製し,trans-シンナムアルデヒドとシクロペンタジエンのDiels-Alder反応においてその触媒活性を検討した。その結果,収率は低いものの,中程度のエナンチオ選択性でDiels-Alder付加体得ることができた。
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    2.亜リン酸エステル-ウレア協働作用型触媒によるエナンチオ選択的ブロモ環化反応の開発
    キラルな亜リン酸エステル-ウレア協働作用型触媒の精密設計に基づき,2-ゲラニルフェノール誘導体のエナンチオ選択的ブロモ環化反応の開発を行った。触媒構造や反応条件を精査した結果,良好なエナンチオ選択性で,対応するブロモ環化生成物を得ることができた。特筆すべきは,2つの環を形成したAB環生成物よりも1つの環のみが形成されたA環生成物の方がエナンチオ選択性が高かったことである。A環生成物が生成する際の遷移状態において,基質のヒドロキシ基と触媒のウレア基とが水素結合を形成することにより,遷移状態の立体配座が適切に制御されたものと考えられる。

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  • Design of High Performance Catalysts Based on Biomimetic Approach

    Grant number:23350039  2011.04 - 2014.03

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

    SAKAKURA Akira

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    Grant amount:\19370000 ( Direct expense: \14900000 、 Indirect expense:\4470000 )

    Based on acid-base combination chemistry, we conducted the rational design of high performance catalysts with functionalities such as weak secondary interaction and acid-base dual activation. Using these catalysts, we developed highly selective synthetic processes. For example, we achieved dehydrative ester condensation in water using organoammonium catalysts, enantioselective carbon-carbon bond forming reactions (Diels-Alder reaction, polyene cyclization and iodolactonization of unsaturated carboxylic acids) and acylation reaction based on acid-base combination catalysis (cyanoethoxycarbonylation of isatins and dehydrative amide condensation of alpha-hydroxy carboxylic acids).

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  • Design of highly functional catalysts based on acid. base combination chemistry

    Grant number:20245022  2008 - 2010

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

    ISHIHARA Kazuaki, SAKAKURA Akira, HATANO Manabu, UYANIK Muhammet

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    Grant amount:\49660000 ( Direct expense: \38200000 、 Indirect expense:\11460000 )

    Rational design of catalysts is very important to control not only reactivity of target reactions but also chemoselectivity, stereoselectivity, regioselectivity, enantioselectivity, and substrate selectivity. Enzymes almost perfectly control target reactions even in vivo. On the other hand, small molecule artificial catalysts cannot perfectly control reactions. In this research project, the development of new acid. base combined catalysts was performed to attain high level of catalytic functions. As results, we succeeded in the development of several high functional catalysts based on acid. base combination chemistry.

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  • カルボン酸の触媒的脱水縮合による酸無水物合成プロセスの開拓

    Grant number:20655019  2008

    日本学術振興会  科学研究費助成事業 萌芽研究  萌芽研究

    坂倉 彰

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    Grant amount:\3600000 ( Direct expense: \3600000 )

    カルボン酸無水物は、DMAP触媒によるエステル化反応を始めとする様々な反応に用いられている有用なアシル化剤である。カルボン酸無水物は、カルボン酸の触媒的脱水縮合で合成されるのが最も理想的である。しかし,これまでのところカルボン酸の直接脱水縮合に有効な触媒は開発されておらず,カルボン酸塩化物やジシクロヘキシルカルボジイミドのような脱水縮合剤を用いるのが一般的である。これらの従来法では,副生成物として腐食性の塩化水素が発生したり,多量の副生成物が生成したりするという問題がある。そこで,本萌芽研究では直接脱水縮合によるカルボン酸無水物の合成に有効な触媒の開発を行った。
    カルボン酸の活性化に有効な触媒を中心に詳細な検討を行った結果,いくつかのアリールボロン酸がカルボン酸間の直接脱水縮合に対して良好な触媒活性を示すことを見出した。特に,2,6位にジアルキルアミノメチル基やトリアルキルアンモニウムメチル基を持つアリールボロン酸が優れた触媒活性を示し,炭化水素などの非極性溶媒中で脱水加熱還流させることにより,対応するカルボン酸無水物が良好な収率で得られた。例えば,2,6-ビス[(N,N-ジイソプロピルアミノ)メチル]フェニルボロン酸触媒(10 mol%)存在下,ピロメリット酸のオクタン溶液を12時間脱水加熱還流させることにより,耐熱性ポリイミド樹脂の原料であるピロメリット酸無水物をほぼ定量的に合成することに成功した。また,低収率ではあるがモノカルボン酸の分子間脱水縮合によるカルボン酸無水物の合成にも成功した。

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  • 生物活性物質合成を指向した環境低負荷型触媒的脱水反応の開拓

    Grant number:18750082  2006 - 2007

    日本学術振興会  科学研究費助成事業 若手研究(B)  若手研究(B)

    坂倉 彰

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    Grant amount:\3700000 ( Direct expense: \3700000 )

    高効率的な触媒的脱水縮合反応(脱水環化反応)の開発およびそれを利用した有用生物活性物質の合成研究を行った。多くの生物活性物質に含まれるチアゾリンは、システイン残基の脱水環化によって合成できるが、C5エキソメチン部位のラセミ化が深刻な問題である。本研究では、このラセミ化を引き起こすことなくシステイン残基の脱水環化を促進できる触媒として、酸化モリブデンービスキノリノラート錯体の開発に成功した。本触媒を用いる合成法により、生物活性物質の合成に有効なチアゾリンやオキサゾリンを含むビルディングブロックが効率よく簡便に合成できる。
    リン酸モノエステルはリン酸とアルコールの触媒的脱水縮合によって合成するのがもっとも理想的である。昨年度開発した過酸化レニウム触媒法に引き続き、新規なリン酸の脱水縮合法の開発を行った結果、ホスファゼン塩基が優れた触媒活性を示し、リン酸モノエステルが選択的に合成できることを見出した。本研究成果は、有機触媒によるリン酸の脱水縮合としての初の成功例であり、核酸塩基部を保護しなくてもヌクレオシドの5'水酸基が選択的にリン酸化できるのが特長である。
    DMAP触媒を用いた酸無水物によるアルコールのアシル化が無塩基・無溶媒条件下で効率よく進行することを見出した。本反応条件下、酸に不安定な3級アルコールや反応性の低いフェノール類、難溶性のポリオールなどのエステルが高収率で合成できた。また、ピバル酸無水物を用いることにより、無塩基・無溶媒条件下でのカルボン酸とアルコールの直接エステル化にも成功した。無塩基・無溶媒で実施できるため、小規模な反応容器で大量のエステルが合成でき、極めて実用性の高いエステル合成法である。

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  • Development of environmentally benign and highly active acid-base catalysts and their synthetic application

    Grant number:15205021  2003 - 2006

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

    ISHIHARA Kazuaki, SAKAKURA Akira, HATANO Manabu

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    Grant amount:\51480000 ( Direct expense: \39600000 、 Indirect expense:\11880000 )

    The design of small but highly functional artificial catalysts is very important for practical organic synthesis. We have succeeded in the rational design of small and simple catalysts and related reactions based on acid-base combination chemistry. Acid-base combined catalysts can be classified into three types: (1) acid-base combined salt catalysts (Type A), (2) conjugate acid-base catalysts (Type B), and (3) non-conjugate acid-base catalysts (Type C):
    1. Acid-base combined salt catalysts (Type A)
    1-1. Bronsted acid-base combined salt catalysts (Type A-1): bulky diarylammonium pentafluorobenzenesulfonates as mild and extremely active dehydrative ester condensation catalysts; chiral ammonium alkanesulfonates as asymmetric Diels-Alder catalysts
    1-2. Lewis acid-base combined salt catalysts and reagents (Type A-2): magnesium ate complexes derived from Grignard reagents and alkyllithium as highly alkyl-selective reagents to ketones; zinc ate complexes as catalysts for the highly alkyl-selective addition of Grignard reagents to ketones and aldimines
    1-3. Cation-anion pair catalysts (Type A-3): lithium N, N-diisopropylamide in Haller-Bauer and Cannizzaro reactions; chiral lithium binaphtholate aqua complex as a highly effective asymmetric catalyst for trimethylsilylcyanation
    1-4. Cation-a complex catalysts (Type A-4): chiral Cu(II)・L-DOPA-derived monopeptide complex as an asymmetric Diels-Alder and Mukaiyama-Michael catalyst
    2. Lewis acid-base conjugate catalysts (Type B): molybdenum oxides as highly effective dehydrative cyclization catalysts directed toward the synthesis of oxazolines and thiazolines (Type B-1(monoconjugation)); zinc(II)・3,3'-diphosphinoyl-BINOLates in the asymmetric addition of organozinc reagents to aldehydes (Type B-2 (triconjugation))
    3. Bronsted acid-Lewis base non-conjugate asymmetric catalysts (separated type) (Type C): L-histidine-derived sulfonamide as a minimal artificial acylase for the kinetic resolution of racemic alcohols
    Thus, we developed new acid-base combined catalysts bearing excellent functions such as dual activation, control of nucleophilicity and basicity, asymmetric induction, hydrophobic effect, and so on. Current research is focused on the development of artificial highly functional catalysts which are superior to natural enzymes.

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  • アクチン脱重合活性をもつ海洋天然有機化合物の探索

    Grant number:15710155  2003 - 2004

    日本学術振興会  科学研究費助成事業 若手研究(B)  若手研究(B)

    坂倉 彰

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    Grant amount:\3700000 ( Direct expense: \3700000 )

    アプリロニンAは海洋動物アメフラシから単離された抗腫瘍性物質である。従来の抗腫瘍性物質とは異なり、細胞骨格タンパク質のアクチンの重合・脱重合に関与することは分かっているが、抗腫瘍活性発現の分子機構は現在のところ不明である。そこで、アクチンとアプリロニンAの結合を化学的に明らかにすることを目的として、以下の研究を行った。活性に重要な側鎖部に光反応基と蛍光基を有するプローブ分子を4種類合成し、光親和性標識実験を行ったところ,1つのプローブ分子において,光標識されたアクチンを電気泳動で検出することに成功した。さらに,アプリロニンAとの競合実験により,プローブ分子がアプリロニンAと同じ位置でアクチンに結合していることを明らかにした。また,アクチン-アプリロニンA複合体の結晶化に成功し,放射光を用いて結晶構造解析を行った。その結果,アプリロニンAはアクチンのサブドメイン1と3の間の脂溶性クレフトに結合することが明らかになった。さらに詳細に複合体の構造を検討したところ,これまで報告されているアクチン脱重合マクロリドとは異なり,ラクトン部がサブドメイン1の方を向いて結合していることが分かった。この特徴的な構造がアプリロニンAの強い抗腫瘍性に関係するものと考えられる。
    また、アプリロニンAと同様にアクチンを脱重合するミカロライドBの側鎖部を合成した。このもののアクチン脱重合活性を測定したところ,アプリロニンAに匹敵する非常に強い活性を示した。

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  • アクチン、ホスファターゼなどの生体高分子と複合する有機化合物の創製と反応

    Grant number:13024215  2001 - 2002

    日本学術振興会  科学研究費助成事業  特定領域研究

    木越 英夫, 坂倉 彰

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    Grant amount:\4200000 ( Direct expense: \4200000 )

    有機小分子と生体高分子との相互作用の研究は有機化合物による分子認識機構を解明するとともに医学・生物学の分野では生物活性物質の作用機構解明や医薬品開発につながる必須の研究領域である。今回、対象生体高分子として細胞骨格タンパク質のアクチンと新型のプロテインホスファターゼに着目した。
    海洋動物アメフラシから単離されたアプリロニンAは、細胞骨格タンパク質のアクチンに作用する新しい型の抗腫瘍性物質である。これまでの知見よりアプリロニンAの側鎖部がアクチン脱重合活性に重要な部分構造であることが判明していたので、アプリロニンAの約十分の一の活性を持つ側鎖部人工類緑体に光アフィニティ官能基を導入した誘導体2種を合成した。これらの化合物とアクチンの反応を行ったところ、アクチンを効率良く標識することが明らかとなった。現在は、標識部位の特定のために、標識体の酵素加水分解と断片の構造を検討している。
    最近、9-アントラセンカルボン酸(9AC)に阻害されるこれまでには知られていない型のプロテインホスファターゼが存在していることが報告された。そこで、9AC誘導体を設計・合成し、これらのブロテインホスファターゼ阻害活性を検定した。その結果、3位にリンカーをつけた誘導体は目的とする酵素を阻害することが分かった。
    新型の海洋産細胞毒性物質ハテルマライドNAの構造確定と標的分子検索を目的として、合成研究を行い、提出していた構造を修正した。

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