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Last Updated :2024/11/22

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Master

Affiliation (Master)

  • Faculty of Science　Chemistry　Organic and Biological Chemistry

Affiliation (Master)

  • Faculty of Science　Chemistry　Organic and Biological Chemistry

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Profile and Settings

Degree

  • PhD（2011/03 The University of Tokyo）
  • Master（2008/03 The University of Tokyo）
  • Bachelor（2006/03 The University of Tokyo）

Profile and Settings

  • Name (Japanese)

    Shimizu

  • Name (Kana)

    Yohei

  • Name

    201801002130749160

Achievement

Research Interests

  • Catalyst   Organic Chemistry   

Research Areas

  • Nanotechnology/Materials / Synthetic organic chemistry / Catalytic Reaction
  • Life sciences / Pharmaceuticals - chemistry and drug development

Research Experience

  • 2023/04 - Today Hokkaido University List Sustainable Digital Transformation Catalyst Collaboration Research Platform, Institute for Chemical Reaction Design and Discovery (ICReDD List-PF) Principal Investigator (PI)
  • 2020/11 - Today Hokkaido University WPI-ICReDD Associate Professor
  • 2020/11 - Today Hokkaido University Faculty of Science Department of Chemistry Associate Professor
  • 2019/04 - 2020/10 Hokkaido University WPI-ICReDD Lecturer
  • 2018/01 - 2020/10 Hokkaido University Faculty of Science Department of Chemistry Lecturer
  • 2015/04 - 2017/12 The University of Tokyo Graduate School of Pharmaceutical Sciences
  • 2011/04 - 2015/03 The University of Tokyo Graduate School of Pharmaceutical Sciences
  • 2008/04 - 2011/03 Japan Society for the Promotion of Science

Education

  • 2006/04 - 2011/03  The University of Tokyo  Graduate School of Pharmaceutical Sciences
  • 2004/04 - 2006/03  The University of Tokyo  Faculty of Pharmaceutical Sciences
  • 2002/04 - 2004/03  The University of Tokyo  Department of Arts and Sciences  Natural Sciences II

Committee Memberships

  • 2019/06 -2020/03   14th International Conference on Cutting-Edge Organic Chemistry in Asia (ICCEOCA-14)   14th International Conference on Cutting-Edge Organic Chemistry in Asia (ICCEOCA-14) Local Organizing Committee

Awards

  • 2023/02 日本化学会北海道支部 2022年度 日本化学会北海道支部奨励賞
     保護基フリー合成を指向した化学選択的触媒反応の開発 
    受賞者: 清水洋平
  • 2020/01 Thieme Chemistry Journals Thieme Chemistry Journals Award
     
    受賞者: Yohei Shimizu
  • 2019/03 The Pharmaceutical Society of Japan The Pharmaceutical Society of Japan Award for Young Scientists
     Development of Chemoselective Reactions by Exploiting Nature of Catalyst 
    受賞者: Yohei Shimizu
  • 2018/03 The Chemical Society of Japan The Chemical Society of Japan Lecture Award
     一価銅触媒の特性を活かした化学選択的反応の開発 
    受賞者: 清水洋平
  • 2015 有機合成化学協会 TORAY Award in Synthetic Organic Chemistry
     ホウ素触媒と遷移金属触媒の協奏的効果によるカルボン酸の化学選択的修飾反応の開発 
    受賞者: Yohei Shimizu
  • 2013/08 ArmChemFront 2013 Best Poster Prize
     In situ catalytic generation of allylcopper species and its direct use for asymmetric allylation 
    受賞者: Yohei Shimizu

Published Papers

  • Asa Tagata, Masaya Sawamura, Yohei Shimizu
    Chemistry Letters 2024/11/20
  • Cheng Peng, Tianle Wu, Xueyan Yang, Mengyao Pei, Siyuan Wang, Motomu Kanai, Yohei Shimizu, Xiaofeng Wei
    Organic Letters 2024/11/18
  • Kai Sun, Yoshito Heike, Masaya Sawamura, Dennis Chung-Yang Huang, Yohei Shimizu
    2024/09/03
  • Yukiho Yoshida, Masaya Sawamura, Yohei Shimizu
    Organic Letters 26 (26) 5425 - 5429 1523-7060 2024/06/19 [Refereed][Not invited]
  • Masaya Sawamura, Yohei Shimizu
    Reference Module in Chemistry, Molecular Sciences and Chemical Engineering 2024 [Refereed][Invited]
  • M. Sawamura, Y. Shimizu
    Knowledge Updates 2024/2 2024 [Refereed][Invited]
     
    Abstract Carboxylic acids are readily available feedstock materials, and are also found in natural products, pharmaceuticals, agrochemicals, and other biologically active compounds. Hence, efficient methods to transform carboxylic acids into other value-added compounds is of great importance. This review is an update to Science of Synthesis Section 20.2.1.8 on the synthesis of carboxylic acids with “retention of the functional group”. The main focus of this review is placed on asymmetric reactions and catalytic reactions, along with practical stoichiometric reactions, reported in the period 2010–2022. The transformations discussed include α-functionalizations, conjugate additions, and C(sp2)—H as well as C(sp3)—H functionalizations.
  • Emna Mejri, Kosuke Higashida, Yuta Kondo, Anna Nawachi, Hiroyuki Morimoto, Takashi Ohshima, Masaya Sawamura, Yohei Shimizu
    Organic Letters 1523-7060 2023/06/08
  • Kai Sun, Chung-Yang Dennis Huang, Masaya Sawamura, Yohei Shimizu
    Synlett 0936-5214 2023/04/11 [Refereed][Invited]
     
    A boron-catalyzed direct α-trifluoromethylthiolation of carboxylic acids was developed. Catalytically generated boron enediolates reacts with electrophilic SCF3 reagent, N-SCF3-phthalimide, to provide α-SCF3 carboxylic acids without the need of substrate pre-activation. The method is applicable to direct modification of bioactive carboxylic acids. Data science analyses provided suitable models for substrate classification as well as yield prediction.
  • Yohei Shimizu, Motomu Kanai
    CHEMICAL RECORD 1527-8999 2023/01 [Refereed][Invited]
     
    Catalytic, chemoselective, and asymmetric alpha-functionalizations of carboxylic acids promise up-grading simple feedstock materials to value-added functional molecules, as well as late-stage structural diversifications of multifunctional molecules, such as drugs and their leads. In this personal account, we describe boron-catalyzed alpha-functionalizations of carboxylic acids developed in our group (five reaction types). The reversible boron carboxylate formation is key to the acidification of the alpha-protons and enolization using mild organic bases, allowing for chemoselective and asymmetric bond formations of carboxylic acids. The ligand effects on reactivity and stereoselectivity, substrate scopes, and mechanistic insights are summarized.
  • Masaya Sawamura, Yohei Shimizu
    European Journal of Organic Chemistry 1434-193X 2022/11/25 [Refereed][Invited]
  • Satoshi Sakai, Akane Fujioka, Koji Imai, Kei Uchiyama, Yohei Shimizu, Kosuke Higashida, Masaya Sawamura
    Advanced Synthesis & Catalysis 364 (14) 2333 - 2339 1615-4150 2022/06/21 [Refereed]
  • Akito Kitabayashi, Sho Mizushima, Kosuke Higashida, Yuto Yasuda, Yohei Shimizu, Masaya Sawamura
    Advanced Synthesis & Catalysis 364 (11) 1855 - 1862 1615-4150 2022/04/27 [Refereed][Not invited]
  • Ibuki Tanaka, Masaya Sawamura, Yohei Shimizu
    Organic Letters 24 (2) 520 - 524 1523-7060 2022/01/21 [Refereed]
  • Ryotaro Niizeki, Kosuke Higashida, Emna Mejri, Masaya Sawamura, Yohei Shimizu
    Synlett 0936-5214 2021/10/19 [Refereed]
     
    A series of neutral C,N,N Au(III) complexes was synthesized with N-(8-quinolinyl)benzamide derivatives and chiral N-(2-(oxazolin-2-yl)phenyl)benzamide derivatives. This convenient synthesis method for amide ligands as well as an operationally simple complexation by direct C-H auration permitted changes to both the steric and electronic properties of the Au(III) complexes for promoting catalytic three-component coupling of an aldehyde, an amine, and an alkyne.
  • Kai Sun, Masato Ueno, Keisuke Imaeda, Kosei Ueno, Masaya Sawamura, Yohei Shimizu
    ACS Catalysis 11 (15) 9722 - 9728 2155-5435 2021/08/06 [Refereed]
  • Hongyu Chen, Shigeru Yamaguchi, Yuya Morita, Hiroyasu Nakao, Xiangning Zhai, Yohei Shimizu, Harunobu Mitsunuma, Motomu Kanai
    2021/05/13 [Refereed][Not invited]
     
    Asymmetric catalysis enabling divergent control of multiple stereocenters remains challenging in synthetic organic chemistry. While machine learning-based optimization of molecular catalysis is an emerging approach, data-driven catalyst design to achieve stereodivergent asymmetric synthesis producing multiple reaction outcomes, such as constitutional selectivity, diastereoselectivity, and enantioselectivity, is unprecedented. Here, we report the straightforward identification of asymmetric two-component iridium/boron hybrid catalyst systems for α-C-allylation of carboxylic acids. Structural optimization of the chiral ligands for iridium catalysts was driven by molecular field-based regression analysis with a dataset containing overall 32 molecular structures. The catalyst systems enabled selective access to all the possible isomers of chiral carboxylic acids bearing contiguous stereocenters. This stereodivergent asymmetric catalysis is applicable to late-stage structural modifications of drugs and their derivatives.
  • Hiroaki Murayama, Yoshito Heike, Kosuke Higashida, Yohei Shimizu, Nuttapon Yodsin, Yutthana Wongnongwa, Siriporn Jungsuttiwong, Seiji Mori, Masaya Sawamura
    Advanced Synthesis & Catalysis 362 (21) 4655 - 4661 1615-4150 2020/11/04 [Refereed]
  • Hiroaki Murayama, Yoshito Heike, Kosuke Higashida, Yohei Shimizu, Nuttapon Yodsin, Yutthana Wongnongwa, Siriporn Jungsuttiwong, Seiji Mori, Masaya Sawamura
    Advanced Synthesis & Catalysis 362 (21) 4445 - 4445 1615-4150 2020/09/15
  • Yohei Shimizu
    Chemical and Pharmaceutical Bulletin 68 (5) 405 - 420 0009-2363 2020/05/01 [Refereed][Invited]
  • Shohei Mimura, Sho Mizushima, Yohei Shimizu, Masaya Sawamura
    Beilstein Journal of Organic Chemistry 16 537 - 543 2020/03/31 [Refereed][Not invited]
     
    © 2020 Mimura et al. A chiral phenol–NHC ligand enabled the copper-catalyzed enantioselective conjugate reduction of α,β-unsaturated esters. The phenol moiety of the chiral NHC ligand played a critical role in producing the enantiomerically enriched products. The catalyst worked well for various (Z)-isomer substrates. Opposite enantiomers were obtained from (Z)- and (E)-isomers, with a higher enantiomeric excess from the (Z)-isomer.
  • Kei Ito, Toshifumi Tatsumi, Kazuki Takahashi, Yohei Shimizu, Kenzo Yamatsugu, Motomu Kanai
    Chemical and Pharmaceutical Bulletin 68 (3) 212 - 215 0009-2363 2020/03/01 [Refereed]
     
    Anti-cancer chemotherapy with good efficacy and fewer side effects is highly desirable. A drug delivery system comprising a cancer-targeting module and a cytotoxic agent connected with a cleavable linker is promising for reducing side effects. The development of a cleavable linker satisfying the requirements of both stability and cleavability, however, is difficult, especially when a carbonate moiety is used for conjugating the linker to a hydroxy group in a drug of interest. We herein report a new stable linker comprising carbamate and ester spacers, which can be introduced on a hydroxy group of a drug. This linker is more stable in aqueous neutral buffer than a corresponding carbonate-type linker, and releases a payload anti-cancer drug, SN-38, through a two-step sequence upon cathepsin B treatment. This linker may have potential use in other drug delivery systems to lower side effects by selectively transporting cytotoxic drugs to tumor cells.
  • Akira SUGIYAMA, Takeshi KAWAMURA, Toshiya TANAKA, Hirofumi DOI, Takefumi YAMASHITA, Keiko SHINODA, Hideaki FUJITANI, Kenzo YAMATSUGU, Yohei SHIMIZU, Toshifumi TATSUMI, Kazuki TAKAHASHI, Motomu KANAI, Eiichi MIZOHATA, Tatsuya KAWATO, Takefumi DOI, Tsuyoshi INOUE, Tatsuhiko KODAMA
    Proceedings of the Japan Academy, Series B 95 (10) 602 - 611 1349-2896 2019/12/11 [Refereed][Not invited]
     
    In advanced cancer patients, malignant cells invade and disseminate within normal cells and develop resistance to therapy with additional genetic mutations, which makes radical cure very difficult. Precision medicine against advanced cancer is hampered by the lack of systems aimed at multiple target molecules within multiple loci. Here, we report the development of a versatile diagnostic and therapeutic system for advanced cancer, named the Cupid and Psyche system. Based on the strong non-covalent interaction of streptavidin and biotin, a low immunogenic mutated streptavidin, Cupid, and a modified artificial biotin, Psyche, have been designed. Cupid can be fused with various single-chain variable fragment antibodies and forms tetramer to recognize cancer cells precisely. Psyche can be conjugated to a wide range of diagnostic and therapeutic agents against malignant cells. The Cupid and Psyche system can be used in pre-targeting therapy as well as photo-immunotherapy effectively in animal models supporting the concept of a system for precision medicine for multiple targets within multiple loci.
  • Yohei Shimizu
    Organic Letters 21 (18) 7466 - 7469 1523-7060 2019/09/05 [Refereed]
  • Ishizawa K, Majima S, Wei XF, Mitsunuma H, Shimizu Y, Kanai M
    The Journal of organic chemistry 84 (17) 10615 - 10628 0022-3263 2019/08 [Refereed][Not invited]
     
    Copper(I)-catalyzed stereodivergent nucleophilic propargylation at the anomeric carbon of unprotected N-acetyl mannosamine was developed using 3-substituted allenylboronates as a nucleophile. The homopropargylic alcohol products contained two contiguous stereocenters, and two stereoisomers out of the four possible isomers were selectively obtained in a catalyst-controlled manner by applying either basic conditions: a MesCu/(R,R,R)-Ph-SKP catalyst with a B(OiPr)3 additive or acidic conditions: a CuBF4/(S,S,S)-Ph-SKP catalyst with an MeB(OiPr)2 additive. Mechanistic studies suggested the presence of distinct active nucleophilic species depending on the conditions: an allenylcopper species under the basic conditions or an allenylboronate activated by the Lewis acidic copper catalyst under the acidic conditions. The propargylation products were concisely transformed into C3-substituted sialic acids in two steps without the use of protecting groups.
  • Imai, K., Takayama, Y., Murayama, H., Ohmiya, H., Shimizu, Y., Sawamura, M.
    Organic Letters 21 (6) 1717 - 1721 1523-7060 2019/03/15 [Refereed][Not invited]
     
    © 2019 American Chemical Society. A copper/prolinol-phosphine chiral catalyst enabled the one-step synthesis of chiral α-alkylidene-β-lactams. Optimization of the chiral ligand for steric and electronic properties realized the highly enantioselective coupling of nitrones and propargyl alcohol derived alkynes. The resulting chiral α-alkylidene-β-lactams served as a platform for various β-lactams via well-established transformations of α,β-unsaturated carbonyl compounds.
  • Xiao-Feng Wei, Takayuki Wakaki, Taisuke Itoh, Hong-Liang Li, Takayoshi Yoshimura, Aya Miyazaki, Kounosuke Oisaki, Miho Hatanaka, Yohei Shimizu, Motomu Kanai
    Chem 5 (3) 585 - 599 2451-9294 2019/03 [Refereed][Not invited]
  • Taisuke Itoh, Yamato Kanzaki, Yohei Shimizu, Motomu Kanai
    Angewandte Chemie - International Edition 57 (27) 8265 - 8269 1521-3773 2018/07/02 [Refereed][Not invited]
     
    We report copper(I)-catalyzed enantio- and diastereodivergent borylative coupling of styrenes and imines to produce enantiomerically-enriched α,β-dibranched γ-boryl amine derivatives. Each of the four possible stereoisomers of the products, derived from the two contiguous stereocenters, was selectively accessible by choosing a proper chiral ligand for the copper catalyst. This method, which combines catalyst-controlled stereodivergency and constitutional divergency derived from the lynchpin motif (i.e., the C−B bond), offers a strategy for addressing the construction of molecular structural diversity concomitant with precise chirality control.
  • Fujita, T., Yamamoto, T., Morita, Y., Chen, H., Shimizu, Y., Kanai, M.
    Journal of the American Chemical Society 140 (18) 5899 - 5903 1520-5126 2018/05/09 [Refereed][Not invited]
     
    We describe herein the asymmetric synthesis of α-allyl carboxylic acids containing an α-quaternary stereocenter by a chiral hybrid catalyst system comprising palladium and boron complexes. The reaction proceeded through palladium-catalyzed ionization of α,α-disubstituted O-allyl esters for the generation of chiral π-allyl palladium complex as an electrophile, boron-catalyzed enolization of the carboxylate part for the generation of chiral α,α-disubstituted carboxylic acid-derived enolates as a nucleophile, and enantioselective coupling between the thus-generated nucleophile and electrophile. Proper combinations of chiral ligands for the boron and palladium catalysts were crucial. The reaction proceeded chemoselectively at the α-position of the carboxylic acid group.
  • Ishizawa, K., Nagai, H., Shimizu, Y., Kanai, M.
    Chemical and Pharmaceutical Bulletin 公益社団法人 日本薬学会 66 (3) 231 - 234 0009-2363 2018/03 [Refereed][Not invited]
     

    A catalytic carboxylic acid-selective aldol reaction with trifluoromethyl ketones was developed. Reversible and selective covalent bond formation between a boron catalyst and a carboxylic acid is key to realizing the unprecedented catalytic aldol reaction of simple carboxylic acids. The reaction proceeded chemoselectively at the α-position of carboxylic acid even in the presence of ketone, ester, or amide functional groups in the donor substrates. The chemoselectivity is beneficial for late-stage derivatizations of biologically relevant compounds, as demonstrated by the conversion of indomethacin and triacetylcholic acid.

  • Wei, X.-F., Xie, X.-W., Shimizu, Y., Kanai, M.
    Journal of the American Chemical Society 139 (13) 4647 - 4650 0002-7863 2017/04 [Refereed][Not invited]
     
    A copper(I)-catalyzed enantioselective addition of enynes to ketones was developed. The method allows facile construction of enantiomerically enriched tertiary alcohols using skipped enynes as stable hydrocarbon pronucleophiles. The combination of a soft copper(I)-conjugated Bronsted base catalyst with a chiral diphosphine ligand, (S,S)-Ph-BPE, enabled chemoselective deprotonation of the skipped enynes in the presence of ketones bearing intrinsically more acidic a-protons. The catalytically generated chiral allylcopper species enantio-, diastereo-, regio-, and chemoselectively reacted with ketones, thereby demonstrating excellent substrate generality with functional group tolerance. The skipped enyne moieties of the pronucleophiles were exclusively converted to cis-conjugated enynes, which will eventually allow for further versatile transformations.
  • XiaoFeng Wei, ShiLiang Shi, XiaoWei Xie, Yohei Shimizu, Motomu Kanai
    ACS CATALYSIS 6 (10) 6718 - 6722 2155-5435 2016/10 [Refereed][Not invited]
     
    We developed a copper(I)-catalyzed diastereoselective incorporation of ketones into unprotected pyranoses. The reactivity was dependent on the bite angle of the diphosphine ligand in the copper catalyst, and we identified an achiral diphosphine ligand L1 bearing an exceptionally large bite angle as the optimal ligand. A copper(I)-conjugated Bronsted base catalyst containing ligand L1 enabled the C-C bond-forming reaction via in situ-generated copper(I) enolate, even in the presence of multiple unprotected hydroxy groups. A variety of ketones were introduced with high diastereoselectivity. The product 2,6-cis-pyrans has many applications for the synthesis of biologically active molecules.
  • Taisuke Itoh, Yohei Shimizu, Motomu Kanai
    JOURNAL OF THE AMERICAN CHEMICAL SOCIETY 138 (24) 7528 - 7531 0002-7863 2016/06 [Refereed][Not invited]
     
    We report the first copper-catalyzed regio- and stereoselective borylalkylation of dialkylsubstituted internal alkynes with bis(pinacolato)diboron and alkyl halides. A catalytically generated borylcopper species containing a novel a pi-accepting N-heterocyclic carbene ligand chemoselectively reacted with unactivated internal alkynes over alkyl halides. The intermediate alkenylcopper species subsequently reacted with alkyl halides, affording the desired products. The copper catalyst differentiated steric demands between the two aliphatic substituents on the C C triple bond of the alkyne substrates to exhibit high regioselectivity from a wide range of alkyne/alkyl halide combinations. This method is useful for the straightforward synthesis of trialkylsubstituted alkenylboronates, i.e., versatile precursors for tetrasubstituted alkenes containing three or four different alkylsubstituents, which are difficult to synthesize by other methods.
  • Yohei Shimizu
    Organic Letters 18 (9) 2276 - 2279 1523-7060 2016/04/22 [Refereed]
  • Xiao-Feng Wei, Yohei Shimizu, Motomu Kanai
    ACS Central Science 2 (1) 21 - 26 2374-7943 2016/01/27 [Refereed]
  • Xiaofeng Wei, Yohei Shimizu, Motomu Kanai
    PROGRESS IN ENANTIOSELECTIVE CU(I)-CATALYZED FORMATION OF STEREOGENIC CENTERS 58 169 - 182 1436-6002 2016 [Refereed][Not invited]
     
    Copper is a ubiquitous element on the earth. Copper catalysts promote a wide variety of reaction types by acting as a Lewis acid, a pi acid, a Bronsted base, or an electron mediator. These features make copper catalysts particularly attractive in modern organic chemistry. In this review, we discuss examples of recent copper (I)-catalyzed asymmetric C-C bond-forming reactions via the addition of soft copper(I)-conjugated carbon nucleophiles to carbonyl electrophiles. Specifically, we focus on the unique orthogonal reactivity of soft copper(I)-conjugated carbon nucleophiles to hard protic functional groups, which would allow for protecting group-minimized molecular synthesis.
  • Structure-based protein engineering for cancer therapy
    Eiichi Mizohata, Tatsuya Kawato, Taisuke Nakayama, Yuji Kado, Tsuyoshi Inoue, Yohei Shimizu, Motomu Kanai, Hirofumi Doi, Akira Sugiyama, Takao Hamakubo, Tasuhiko Kodama
    2015/12 [Not refereed][Invited]
  • Taisuke Itoh, Takumi Matsueda, Yohei Shimizu, Motomu Kanai
    CHEMISTRY-A EUROPEAN JOURNAL 21 (45) 15955 - 15959 0947-6539 2015/11 [Refereed][Not invited]
     
    The first regiodivergent oxyboration of unactivated terminal alkenes is reported, using copper alkoxide as a catalyst, bis(pinacolato)diboron [(Bpin)(2)] as a boron source, and (2,2,6,6-tetramethylpiperidin-1-yl)oxyl (TEMPO) as an oxygen source. The reaction is compatible with various functional groups. Two regioisomers are selectively produced by selecting the appropriate ligands on copper. The products may be used as a linchpin precursor for various other functionalizations, and net processes such as carbooxygenation, aminooxygenation, and dioxygenation of alkenes can be achieved after CB bond transformations. Mechanistic studies indicate that the reaction involves the following steps: 1)Transmetalation between CuOtBu and (Bpin)(2) to generate a borylcopper species; 2)regiodivergent borylcupration of alkenes; 3)oxidation of the thus-generated CCu bond to give an alkyl radical; 4)trapping of the resulting alkyl radical by TEMPO.
  • Motomu Kanai, Yohei Shimizu, Yuya Morita, Tomohiro Yamamoto, Hideoki Nagai
    SYNTHESIS-STUTTGART 47 (19) A140 - A143 0039-7881 2015/10 [Refereed][Not invited]
  • Motomu Kanai, Yohei Shimizu, Yuya Morita, Tomohiro Yamamoto, Hideoki Nagai
    SYNLETT 26 (16) A140 - A143 0936-5214 2015/10 [Refereed][Not invited]
  • Tatsuya Kawato, Eiichi Mizohata, Yohei Shimizu, Tomohiro Meshizuka, Tomohiro Yamamoto, Noriaki Takasu, Masahiro Matsuoka, Hiroyoshi Matsumura, Tatsuhiko Kodama, Motomu Kanai, Hirofumi Doi, Tsuyoshi Inoue, Akira Sugiyama
    Journal of biochemistry 157 (6) 467 - 75 0021-924X 2015/06 [Refereed][Not invited]
     
    For a multistep pre-targeting method using antibodies, a streptavidin mutant with low immunogenicity, termed low immunogenic streptavidin mutant No. 314 (LISA-314), was produced previously as a drug delivery tool. However, endogenous biotins (BTNs) with high affinity (Kd < 10(-10) M) for the binding pocket of LISA-314 prevents access of exogenous BTN-labelled anticancer drugs. In this study, we improve the binding pocket of LISA-314 to abolish its affinity for endogenous BTN species, therefore ensuring that the newly designed LISA-314 binds only artificial BTN analogue. The replacement of three amino acid residues was performed in two steps to develop a mutant termed V212, which selectively binds to 6-(5-((3aS,4S,6aR)-2-iminohexahydro-1H-thieno[3,4-d]imidazol-4-yl)pentanamido)hexanoic acid (iminobiotin long tail, IMNtail). Surface plasmon resonance results showed that V212 has a Kd value of 5.9 × 10(-7) M towards IMNtail, but no binding affinity for endogenous BTN species. This V212/IMNtail system will be useful as a novel delivery tool for anticancer therapy.
  • Yuya Morita, Tomohiro Yamamoto, Hideoki Nagai, Yohei Shimizu, Motomu Kanai
    JOURNAL OF THE AMERICAN CHEMICAL SOCIETY 137 (22) 7075 - 7078 0002-7863 2015/06 [Refereed][Not invited]
     
    The carboxyl group (CO OH) is an omnipresent functional group in organic molecules, and its direct catalytic activation represents an attractive synthetic method. Herein) we describe the first example of a direct catalytic nudeophilic activation of carboxylic acids with BH3 center dot SMe2, after which the acids are able to act as carbon nucleophiles, i.e. enolates, in Mannich-type reactions. This reaction proceeds with a mild organic base (DBU) and exhibits high levels of functional group tolerance. The boron catalyst is highly chemoselective toward the COOH group, even in the presence of other carbonyl moieties, such as amides, esters, or ketones. Furthermore, this catalytic method can be extended to highly enantioselective Mannich-type reactions by using a (R)-3,3'-I-2-BINOL-substituted boron catalyst.
  • Tomohiro Yamamoto, Kiyoshi Aoki, Akira Sugiyama, Hirofumi Doi, Tatsuhiko Kodama, Yohei Shimizu, Motomu Kanai
    Chemistry, an Asian journal 10 (4) 1071 - 8 1861-4728 2015/04 [Refereed][Not invited]
     
    Two new biotin analogues, biotin carbonate 5 and biotin carbamate 6, have been synthesized. These molecules were designed to reversibly bind with streptavidin by replacing the hydrogen-bond donor NH group(s) of biotin's cyclic urea moiety with oxygen. Biotin carbonate 5 was synthesized from L-arabinose (7), which furnishes the desired stereochemistry at the 3,4-cis-dihydroxy groups, in 11% overall yield (over 10 steps). Synthesis of biotin carbamate 6 was accomplished from L-cysteine-derived chiral aldehyde 33 in 11% overall yield (over 7 steps). Surface plasmon resonance analysis of water-soluble biotin carbonate analogue 46 and biotin carbamate analogue 47 revealed that KD values of these compounds for binding to streptavidin were 6.7×10(-6)  M and 1.7×10(-10)  M, respectively. These values were remarkably greater than that of biotin (KD =10(-15)  M), and thus indicate the importance of the nitrogen atoms for the strong binding between biotin and streptavidin.
  • Motomu Kanai, Yohei Shimizu, Yuya Morita, Tomohiro Yamamoto, Hideoki Nagai
    Journal of Dynamic Systems, Measurement and Control, Transactions of the ASME 26 (16) A140 - A143 1528-9028 2015 [Refereed][Not invited]
     
    A study was conducted to investigate chemoselective boron-catalyzed nucleophilic activation of carboxylic acids for mannich-type reactions. The catalytically and chemoselectively generated enolates from carboxylic acids were trapped by N-tosyl imines through Mannich-type reaction. The researchers engaged in the study also isolated the products after protection of the carboxylic acids as esters for further investigations.
  • Tatsuya Kawato, Eiichi Mizohata, Yohei Shimizu, Tomohiro Meshizuka, Tomohiro Yamamoto, Noriaki Takasu, Masahiro Matsuoka, Hiroyoshi Matsumura, Tatsuhiko Kodama, Motomu Kanai, Hirofumi Doi, Tsuyoshi Inoue, Akira Sugiyama
    Bioscience, biotechnology, and biochemistry 79 (4) 640 - 2 0916-8451 2015 [Refereed][Not invited]
     
    The streptavidin/biotin interaction has been widely used as a useful tool in research fields. For application to a pre-targeting system, we previously developed a streptavidin mutant that binds to an iminobiotin analog while abolishing affinity for natural biocytin. Here, we design a bivalent iminobiotin analog that shows 1000-fold higher affinity than before, and determine its crystal structure complexed with the mutant protein.
  • Yohei Shimizu, Motomu Kanai
    TETRAHEDRON LETTERS 55 (28) 3727 - 3737 0040-4039 2014/07 [Refereed][Invited]
     
    Copper-catalyzed difunctionalization of unactivated carbon-carbon multiple bonds involving a carbon-carbon bond formation process is reviewed. Carboamination, carbooxygenation, carboboration, and other difunctionalization reactions of alkenes, alkynes, and allenes are described. (C) 2014 The Authors. Published by Elsevier Ltd.
  • Taisuke Itoh, Yohei Shimizu, Motomu Kanai
    ORGANIC LETTERS 16 (10) 2736 - 2739 1523-7060 2014/05 [Refereed][Not invited]
     
    A copper(II)-catalyzed intermolecular three-component oxyarylation of allenes using arylboronic acids as a carbon source and TEMPO as an oxygen source is described. The reaction proceeded under mild conditions with high regio- and stereo-selectivity and functional group tolerance. A plausible reaction mechanism is proposed, involving carbocupration of allenes, homolysis of the intervening allylcopper(II), and a radical TEMPO trap.
  • Yohei Shimizu, Kouji Yasuda, Motomu Kanai
    HETEROCYCLES 88 (2) 919 - 927 0385-5414 2014/01 [Refereed][Not invited]
     
    A catalytic method to construct multi-functionalized isotetronic acids was developed using cyclic hemiacetals and pyruvic acid derivatives as substrates. The key to success was the combination of catalytic amounts of iron(III) trifluoroacetate and 2-mercaptopyridine. A catalytic asymmetric variant was also developed using 6,6'-dimethoxy-binaphthyl phosphate instead of 2-mercaptopyridine.
  • Prasanna Kumara Chikkade, Yohei Shimizu, Motomu Kanai
    CHEMICAL SCIENCE 5 (4) 1585 - 1590 2041-6520 2014 [Refereed][Not invited]
     
    A catalytic enantioselective method for the synthesis of 2-(2-hydroxyethyl) indole scaffolds was developed. The process includes catalytic intramolecular amido-cupration of an allene to generate a novel allylcopper species, followed by asymmetric addition of the thus-generated chiral nucleophile to aldehydes and ketones. This is the first example of catalytic indole formation coupled with asymmetric C-C bond formation via in situ generation of a reactive chiral allylcopper species.
  • Yasuaki Kimura, Soichi Ito, Yohei Shimizu, Motomu Kanai
    ORGANIC LETTERS 15 (16) 4130 - 4133 1523-7060 2013/08 [Refereed][Not invited]
     
    A copper(I)-catalyzed anomeric aminoalkynylation reaction of unprotected aldoses was realized. Use of an electron-deficient phosphine ligand, boric acid to stabilize the iminium intermediate, and a protic additive (IPA) to presumably enhance reversible carbohydrate-boron complexation were all essential for efficient conversion. The reaction proceeded well even with a natural disaccharide substrate, suggesting that the developed catalytic reaction could be useful for the synthesis of glycoconjugates with minimum use of protecting groups.
  • Junya Kawai, Prasanna Kumara Chikkade, Yohei Shimizu, Motomu Kanai
    ANGEWANDTE CHEMIE-INTERNATIONAL EDITION 52 (28) 7177 - 7180 1433-7851 2013/07 [Refereed][Not invited]
  • Motomu Kanai, Shigeki Matsunaga, Kounosuke Oisaki, Yohei Shimizu
    JOURNAL OF SYNTHETIC ORGANIC CHEMISTRY JAPAN 71 (5) 433 - 442 0037-9980 2013/05 [Refereed][Not invited]
     
    In general, biologically active drug lead molecules are structurally complex, bearing multiple functional groups and chiral sp(2) carbons. Our aim in developing new catalysis is to promote a concise, robust, and clean drug lead synthesis. To do so requires catalysis allowing for the design of concepually new retrosynthesis independent of functional groups. Here we summarize our first step toward such a goal. First, we describe a Cu (I) -catalyzed enantioselective condensation of ketones and hemiaminals that can produce versatile chiral building blocks for alkaloid synthesis. The hard anion-conjugated soft metal (HASM) catalysis concept is the basis for the reactivity. Second, two Cu-catalyzed cross-dehydrogenative coupling (CDC) reactions are discussed. The radical-conjugated redox catalysis (RCRC) concept leads to the development of a very early example of catalytic asymmetric aerobic CDC. Third, the Rh-catalyzed aldehyde cross aldol reaction and the Co-catalyzed C-4 selective alkylation of pyridines, both of which are mediated by means of hydride transfer, are described. Unique reactivity in the latter two topics is partly due to the redox activity of the transition metal catalysts.
  • Yohei Shimizu
    ファルマシア 公益社団法人 日本薬学会 49 (7) 695 - 695 2189-7026 2013
  • Shi-Liang Shi, Xiao-Feng Wei, Yohei Shimizu, Motomu Kanai
    JOURNAL OF THE AMERICAN CHEMICAL SOCIETY 134 (41) 17019 - 17022 0002-7863 2012/10 [Refereed][Not invited]
     
    A general catalytic enantioselective method that can produce five-, six-, and seven-membered N-heterocycles possessing various ketone moieties starting from stable and easily available cyclic hemiaminals and ketones was developed. The method involves three successive steps in one pot (aldol addition, dehydration, and enantioselective intramolecular aza-Michael reaction), all of which are promoted by a chiral copper(I)-conjugated Bronsted base catalyst. This method is useful for rapid access to versatile chiral building blocks for the synthesis of drug-lead alkaloids.
  • Shohei Majima, Yohei Shimizu, Motomu Kanai
    TETRAHEDRON LETTERS 53 (33) 4381 - 4384 0040-4039 2012/08 [Refereed][Not invited]
     
    alpha-Alkylation of ketones with styrene derivatives was developed using a mesitylcopper-dppp complex as a soft Bronsted base catalyst. No waste derived from the alkylating reagent was produced in this catalytic alkylation reaction. The bisphosphine ligand structure, as well as the reaction solvent, had profound effects on catalyst activity. The reaction proceeded under mild conditions from a range of ketones and styrene derivatives. The present catalysis is especially useful for the selective mono-alkylation of ketones. (c) 2012 Elsevier Ltd. All rights reserved.
  • Yohei Shimizu, Shi-Liang Shi, Hiroyuki Usuda, Motomu Kanai, Masakatsu Shibasaki
    TETRAHEDRON 66 (33) 6569 - 6584 0040-4020 2010/08 [Refereed][Not invited]
     
    The first catalytic asymmetric total synthesis of ent-hyperforin was described here in detail. Keys to the success were a catalytic asymmetric Diels-Alder reaction, a stereoselective Clasien rearrangement, an intramolecular aldol cyclization, and a vinylogous Pummerer rearrangement. Along with the successful synthetic route, several attempted approaches toward the construction of bicyclo[3.3.1] core and the C2 oxidation were discussed. (C) 2010 Elsevier Ltd. All rights reserved.
  • Yutaka Saga, Rie Motoki, Sae Makino, Yohei Shimizu, Motomu Kanai, Masakatsu Shibasaki
    JOURNAL OF THE AMERICAN CHEMICAL SOCIETY 132 (23) 7905 - + 0002-7863 2010/06 [Refereed][Not invited]
     
    The first asymmetric synthesis of a very promising antituberculosis drug candidate, R207910, was achieved by developing two novel catalytic transformations; a catalytic enantioselective proton migration and a catalytic diastereoselective allylation of an intermediate alpha-chiral ketone. Using 2.5 mol % of a Y-catalyst derived from Y(HMDS)(3) and the new chiral ligand 9, 1.25 mol % of p-methoxypyridine N-oxide (MEPO), and 0.5 mol % of Bu(4)NCl, a-chiral ketone 3 was produced from enone 4 with 88% ee. This reaction proceeded through a catalytic chiral Y-dienotate generation via deprotonation at the gamma-position of 4, followed by regio- and enantioselective protonation at the a-position of the resulting dienolate. Preliminary mechanistic studies suggested that a Y: 9: MEPO = 2: 3: 1 ternary complex was the active catalyst. Bu4NC1 markedly accelerated the reaction without affecting enantioselectivity. Enantiomerically pure 3 was obtained through a single recrystallization. The second key catalytic altylation of ketone 3 was promoted by CuF center dot 3PPh(3)center dot 2EtOH (10 mot %) in the presence of KO(t)Bu (15 mol %), ZnCl(2) (1 equiv), and Bu(4)PBF(4) (1 equiv), giving the desired diastereomer 2 in quantitative yield with a 14: 1 ratio without any epimerization at the a-stereocenter. It is noteworthy that conventional organometallic addition reactions did not produce the desired products due to the high steric demand and a fairly acidic a-proton in substrate ketone 3. This first catalytic asymmetric synthesis of R207910 includes 12 longest linear steps from commercially available compounds with an overall yield of 5%.
  • Yohei Shimizu, Shi-Liang Shi, Hiroyuki Usuda, Motomu Kanai, Masakatsu Shibasaki
    ANGEWANDTE CHEMIE-INTERNATIONAL EDITION 49 (6) 1103 - 1106 1433-7851 2010 [Refereed][Not invited]
  • Yao Du, Li-Wen Xu, Yohei Shimizu, Kounosuke Oisaki, Motomu Kanai, Masakatsu Shibasaki
    JOURNAL OF THE AMERICAN CHEMICAL SOCIETY 130 (48) 16146 - + 0002-7863 2008/12 [Refereed][Not invited]
     
    A highly diastereoselective reductive Mannich coupling of ketimines and alpha,beta-unsatLirated esters was developed using CuOAc-PPh(3) or CLOAc-MePPh(2) complex as a catalyst (5 mol %) and pinacolborane as a reducing reagent, The reaction was easily conducted at room temperature, and the substrate generality was broad. This platform methodology was extended to the first catalytic asymmetric reductive Mannich reaction of ketimines using CuOAc-DIFLUORPHOS as the catalyst (10 mol %). Switching the reducing reagent from pinacolborane to (EtO)(3)SiH was key to inducing the high enantioselectivity (82-93% ee). High diastereoselectivity was also maintained (3:1 similar to 30:1). Thus, products containing contiguous tetra- and trisubstituted carbons were catalytically synthesized with high stereoselectivities. Products were converted to alpha,beta,beta-trisubstituted (beta(2,3,3)) amino acid derivatives without any racemization and epimerization through simple treatment under acidic conditions. This method is the first entry of the catalytic asymmetric synthesis of beta(2,3,3)-amino acid derivatives, which constitute important chiral building blocks of biologically significant molecules.
  • Yohei Shimizu, Akiyoshi Kuramochi, Hiroyuki Usuda, Motomu Kanai, Masakatsu Shibasaki
    TETRAHEDRON LETTERS 48 (24) 4173 - 4177 0040-4039 2007/06 [Refereed][Not invited]
     
    A highly congested bicyclo[3.3.]nonanone core of polycyclic polyprenylated acylphloroglucinols was constructed using a stereoselective Claisen rearrangement and an intramolecular aldol reaction as the key steps. The stereochemistry of C-4 appeared to control the ground state conformation of the cyclohexenone core, which determined the diastereoselectivity in the Claisen rearrangement. (c) 2007 Elsevier Ltd. All rights reserved.
  • Kuramochi Akiyoshi, Shimizu Yohei, Usuda Hiroyuki, Yamatsugu Kenzo, Kanai Motomu, Shibasaki Masakatsu
    International Symposium on the Chemistry of Natural Products 天然有機化合物討論会 2006 "P - 270" 2006/07/23

MISC

  • 杉山暁, 杉山暁, 山次健三, 巽俊文, 鷲山幸信, 金井求, 児玉龍彦, 清水洋平, 溝端栄一, 井上豪  核医学(Web)  57-  (Supplement)  2020
  • 巽俊文, 山次健三, 清水洋平, 杉山暁, 趙松吉, 粟生木美穂, 西嶋剣一, 右近直之, 高橋和弘, 児玉龍彦, 鷲山幸信, 金井求  反応と合成の進歩シンポジウム講演要旨集  2020
  • Wei Xiaofeng, Shimizu Yohei, Kanai Motomu  Symposium on the Chemistry of Natural Products, symposium papers  57-  (0)  2015  [Not refereed][Not invited]
     
    <p>Sialic acids represent one of the most important constituents of glycoconjugates in biological system. Thus, rapid and scalable supply and broadening the structural diversity of sialic acids are an urgent demand in the current glycochemistry and glycobiology. Despite significant improvement on synthetic efficiency during past decades, there are still several points to be overcome: limited scope, unsatisfactory yield and scalability. Moreover, the flexibility in structural and stereochemical alternation are limited.</p><p>To realize efficient and scalable synthesis of wide variety of natural and unnatural sialic acid derivatives, we developed a copper-catalyzed propargylation of unprotected aldoses. The reaction proceeded in high yield and high diastereoselectivity even in a gram-scale. In addition, the diastereoselectivity of the reaction could be switched by changing the ligand's stereochemistry. Variety of aldoses were applicable (13 examples) including a disaccharide, b-D-lactose. The products could be converted to the corresponding sialic acids through a simple three-step sequence.</p>
  • 清水 洋平  ファルマシア  49-  (7)  695  -695  2013  [Not refereed][Not invited]
  • Shimizu Yohei, Shi Shiliang, Usuda Hiroyuki, Kanai Motoumu, Shibasaki Masakatsu  Proceedings of the Symposium on Progress in Organic Reactions and Syntheses  35-  (0)  83  -83  2009  [Not refereed][Not invited]
     
    Hyperforin was isolated from western herb, St. John's wort (<I>Hypericum perforatum</I>). Hyperforin exhibits various biologic activities including mild anti-depressant activity, anti-malarial activity, inhibitory activity of human histone deacetylase, and CYP3A4 induction activity. And this compound has characteristic structure; highly substituted bicyclo[3.3.1]nonanone core, 4 asymmetric carbon center.<BR> To synthesize attractive natural compound, hyperforin, our group developed the catalytic asymmetric Diels-Alder reaction. This key reaction gave substituted cyclohexene which has 2 contiguous asymmetric centers in high yield and selectivity (93% yield, 96% ee, exo: endo = >33: 1).<BR> From this key intermediate, we already synthesized bicyclo core via Claisen rearrangement, intramolecular aldol cyclization as key intermediate.<BR> And model study revealed that additional oxidation was possible using vinylogous Pummerer rearrangement.

Presentations

  • Enabling Direct Functionalization of Carboxylic Acids by Boron Catalysis  [Invited]
    Yohei Shimizu
    The 2nd List Platform Symposium  2024/08
  • Visible Light-Driven Boron-Catalyzed Direct Functionalization of Carboxylic Acids  [Invited]
    Yohei Shimizu
    ICAT International Symposium on Catalysis 2024: Sustainable synthesis by use of efficient catalyst  2024/07
  • α-Functionalization of Carboxylic Acids Driven by Boron Catalyst and Visible Light  [Invited]
    Yohei Shimizu
    7th International Conference on Catalysis and Chemical Engineering  2023/02
  • 保護基フリー合成を指向した化学選択的触媒反応の開発  [Invited]
    清水洋平
    2022年度日本化学会北海道支部奨励賞 受賞講演会  2023/02
  • Development of Chemoselective Reactions Using Boron Catalyst and Photoirradiation  [Invited]
    Yohei Shimizu
    Hybrid Catalysis若手道場 online  2022/03
  • Development of Chemoselective Reactions Using Copper and Boron as Key Catalysts  [Invited]
    Yohei Shimizu
    LHFA virtual lecture, Université Toulouse III  2021/10
  • Chemoselective α-Functionalization of Carboxylic Acids  [Invited]
    Yohei Shimizu
    2020 Dalian University of Technology-Overseas Partner Universities Series Online Exchange Conference  2021/01
  • Carboxylic acid-selective α-functionalization enabled by boron activator  [Invited]
    Yohei Shimizu
    The 11th CSE Autumn School & The 8th ALP International Symposium  2020/11
  • Boron-Catalyzed α-Functionalization of Carboxylic Acids  [Invited]
    Yohei Shimizu
    Hokkaido mini-Symposium by Young Generations in Asia  2019/11
  • Carboxylic Acid-Selective Enolate Formation  [Invited]
    Yohei SHIMIZU
    Hokkaido Summer Symposium 2019 on Catalysis for Organic Synthesis  2019/07  Hokkaido University
  • 触媒の特性を活かした化学選択的反応の開発  [Invited]
    Yohei SHIMIZU
    日本薬学会第139年会 奨励賞受賞講演  2019/03  Chiba 
    受賞講演
  • 触媒の特性を活かした化学選択的反応の開発  [Invited]
    Yohei SHIMIZU
    若手研究者のための有機化学札幌セミナー  2018/11  Hokkaido University
  • 一価銅触媒の特性を活かした化学選択的反応の開発  [Invited]
    Yohei SHIMIZU
    日本化学会 第98春季年会 若い世代の特別講演会  2018/03  日本大学船橋キャンパス
  • 一価銅触媒の特性を活かした化学選択的反応の開発  [Invited]
    Yohei SHIMIZU
    第二回有機若手ワークショップ  2017/11  Kyoto University
  • 触媒の特性を活かした化学選択的反応の開発  [Invited]
    清水洋平
    第12回神戸大学有機反応化学研究会  2017/11
  • 触媒の特性を活かした化学選択的反応の開発  [Invited]
    Yohei SHIMIZU
    平成29年度若手研究者のためのセミナー  2017/07  The University of Tokyo
  • Chemoselective C-C Bond Forming Reactions  [Not invited]
    Yohei Shimizu
    University of California Santa Barbara  2017/06
  • Chemoselective C-C Bond Forming Reactions  [Not invited]
    Yohei SHIMIZU
    Chalmers University of Technology  2017/04  Chalmers University of Technology
  • ホウ素触媒によるカルボン酸の化学選択的求核的活性化法の開発  [Invited]
    Yohei SHIMIZU
    日本薬学会第137年会 有機合成化学の若い力  2017/03  Tohoku University
  • 触媒の特性を活かした化学選択的反応の開発  [Invited]
    Yohei SHIMIZU
    第40回 星薬科大学大学院研究科助手会・大学院自治会 合同公開セミナー  2016/11  星薬科大学
  • 保護基フリー合成を目指した化学選択的反応の開発  [Invited]
    Yohei SHIMIZU
    有機触媒若手セミナー  2015/10  Nagoya
  • Copper-Catalyzed C-C Bond Forming Reactions Utilizing Its “Soft” Characteristics  [Not invited]
    Yohei SHIMIZU
    University of Alberta  2014/07  University of Alberta
  • ent-Hyperforinの触媒的不斉全合成  [Invited]
    Yohei SHIMIZU
    若手研究者のためのセミナー(2010)  2010/09  Chiba University

Teaching Experience

  • 教科教育法 理科I教科教育法 理科I Hokkaido University
  • 現代有機化学演習現代有機化学演習 Hokkaido University
  • 分子化学A分子化学A Hokkaido University
  • Hokkaido Summer Institute, Leading and Advanced Biological and Polymer Chemistry and Engineering IIIHokkaido Summer Institute, Leading and Advanced Biological and Polymer Chemistry and Engineering III Hokkaido University

Association Memberships

  • 触媒学会   THE SOCIETY OF SYNTHETIC ORGANIC CHEMISTRY, JAPAN   THE PHARMACEUTICAL SOCIETY OF JAPAN   THE CHEMICAL SOCIETY OF JAPAN   

Research Projects

  • Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research
    Date (from‐to) : 2024/04 -2026/03 
    Author : 清水 洋平
  • Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research Grant-in-Aid for Challenging Research (Exploratory)
    Date (from‐to) : 2022/06 -2024/03 
    Author : 清水 洋平
     
    塩素ラジカルとホスフィン触媒の相互作用を活用したC-Hアミノ化反応について検討を行った。可視光領域に吸収帯を持つ塩化セリウム触媒を用いることで触媒的に塩素ラジカルを生成する反応条件を採用し、ホスフィン触媒およびアミノ化剤の探索を行った。その結果、アゾジカルボン酸エステルをアミノ化剤として用いた際にC-Hアミノ化が進行し、ホスフィン触媒の構造や電子的効果によってC-Hアミノ化の位置選択性が変化することが明らかとなった。とりわけビアリール骨格を有するホスフィン触媒が良好な結果を示しており、ホスフィン触媒の立体的な影響があるのではないかと考えられる。また、溶媒効果も顕著であり、ハロゲン系溶媒が効果的である。これらの結果は、高反応性の塩素ラジカルをホスフィン触媒の作用によって制御したものだと考えられる。 また、上記のC-Hアミノ化反応を検討する中で、塩素ラジカルを必要としない新たなC-Hアミノ化反応を見出した。ホスフィンを触媒として、塩基性条件下、アミノ化剤と基質を0℃～室温条件で撹拌することによって位置選択的に反応が進行する。いくつかのホスフィン触媒を検討したところ、本反応においてもその構造や電子的効果が反応の効率に大きく影響することがわかった。現段階では、再現性に問題が残っているものの、テトラヒドロキノリンを基質としたモデル反応で、最高90％収率程度で目的物が得られる。また、この触媒条件をいくつかの基質に適用したところ、ピリジン部位を持つ基質で特異的に反応が進行した。
  • Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research Grant-in-Aid for Transformative Research Areas (A)
    Date (from‐to) : 2022/06 -2024/03 
    Author : 清水 洋平
     
    独自の技術である、ホウ素触媒を用いたカルボン酸のエノラート生成法に光励起を組み合わせることでβ位アリル化反応の開発を検討した。2021年に論文発表したカルボン酸α位アリル化の副生成物としてわずかに得られていたβ位アリル化体の生成比率向上を目指し、ホウ素触媒の配位子、塩基、およびアリル化剤の構造を行った。塩基、アリル化剤は従来と同じ化合物が適切であった一方で、配位子はBINOL型配位子を単体で用いるよりもBINOL型配位子とアミノ酸型配位子を組み合わせた条件で収率が向上することが分かった。カルボン酸エノラートの生成に二つのホウ素触媒が関与しているという想定反応機構に照らして考えると、カルボン酸エノラートの生成と光励起およびC-C結合形成段階に二種類の配位子が協奏的に関与していることを示唆するものであると考えられる。そこで、最適配位子を探索するために、まずBINOL型配位子のデータベースの構築に取り組んだ。合成済み配位子34個と多数の配位子候補についてDFT計算を実施し、それぞれの配位子の様々なパラメータを求め、機械学習における記述子として利用できるように整理した。一方で、実際に合成したBINOL型配位子34個を用いて、β位アリル化反応を実施し、収率を求めた。この実験的データとDFT計算によって得られた様々な記述子を用いてモデル構築を検討した。現在までに配位子構造から収率を予測する精度は低いため、いくつかの配位子候補を合成して実験データを拡充して収率予測モデルの精度を向上させる予定である。
  • Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (B)
    Date (from‐to) : 2020/04 -2023/03 
    Author : Shimizu Yohei
     
    A novel direct α-functionalization of carboxylic acids was developed by utilizing boron catalysts and visible light energy. One-electron transfer with a reactant proceeds from a photoexcited boron enolate in the reaction system, and a bond formation reaction at the α-position of the carboxylic acid proceeds via a radical intermediate. The α-allylation reaction, which is a carbon chain introduction reaction, and the α-amination reaction, which is a heteroatom introduction reaction, were developed, and the versatility of this method was demonstrated.
  • Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research on Innovative Areas (Research in a proposed research area)
    Date (from‐to) : 2020/04 -2022/03 
    Author : 清水 洋平
     
    これまで独自に発展させてきたホウ素触媒によるカルボン酸のエノラート生成法を基盤として、光照射によるエノラートの励起を組み込むことで触媒的ラジカル反応の開発に成功した。 カルボン酸を基質とした触媒的ラジカル反応は、副反応として脱炭酸が容易に進行してしまうために開発が進んでこなかった分野である。本研究では、ホウ素エノラートが光励起されることによってはじめて1電子移動が起こるという機構でラジカル反応が開始されるため、脱炭酸が起こらず、カルボン酸α位での修飾反応が進行する。ホウ素上の配位子構造が反応の進行に大きな影響を与えていることがわかったため、さまざまな構造の配位子を合成し、検討を行った。その結果、広いπ共役系を有する配位子を用いるほど高効率に反応が進行することが明らかとなった。最適配位子をもとに基質一般性の検討を行ったところ、様々なαアリールカルボン酸に適用可能であった。また、エステルやケトン存在下にもカルボン酸α位のみで反応が進行する化学選択性を有することも確認できた。 上記の光駆動型反応に加えて、オレフィンとカルボン酸から一挙にラクトンを形成する、新たな反応の初期的知見を得ることができた。ホウ素触媒存在下、適切な活性化剤を添加するとカルボン酸α位での炭素－炭素結合形成とカルボン酸酸素原子とオレフィンとの酸素－炭素結合が一挙に形成される。現在のところ反応機構は不明であるが、ホウ素触媒非存在下ではラクトン形成は進行しないことがわかっている。
  • Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research Grant-in-Aid for Early-Career Scientists
    Date (from‐to) : 2018/04 -2020/03 
    Author : Shimizu Yohei
     
    In this research project, we were able to achieve the following two results: (1) discovery of boron-catalyzed α-allylation of carboxylic acids in combination with visible light irradiation, and (2) development of boron-catalyzed α-amination of carboxylic acids. In the first achievement, we were able to discover a new reactivity of boron catalysis, and it will be the basis for expanding the application to more diverse reaction systems. In the second achievement, we established a method for synthesizing sterically hindered α-amino acids , which is difficult to synthesize by other methods. This method would accelerate the application of unnatural amino acids to various field by supplying order-made amino acids.
  • Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)
    Date (from‐to) : 2015/04 -2019/03 
    Author : Shimizu Yohei
     
    We developed copper-catalyzed stereodivergent propargylation of unprotected aldoses. The C-C bond forming reaction proceeds preferentially over protonolysis of organocopper species even in the presence of multiple free hydroxy groups. Moreover, the diastereoselectivity of the product can be switched depending on the chirality of the copper catalyst. The product could be transformed to sialic acid derivatives in only three steps.
  • 化学選択的カルボン酸α位修飾反応の開発
    アステラス病態代謝研究会：研究助成金
    Date (from‐to) : 2016/12 -2017/11 
    Author : 清水洋平
  • Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research Grant-in-Aid for Young Scientists (B)
    Date (from‐to) : 2013/04 -2015/03 
    Author : SHIMIZU Yohei
     
    We developed a novel method to generate allylcopper species from an allenylanilide, which possesses both an allene moiety and an aniline moiety in one molecule. Cu(I) catalyst facilitates a generation of allylcopper species along with formation of indole structure. The generated allylcopper species can work as nucleophile to various carbonyl compounds including ketones. The reaction proceeded in enantioselective manner by utilizing a chiral diphosphine ligand. Thus the reaction produced chiral 2-(2-hydroxyethyl)indoles efficiently, whose scaffold is difficult to construct by other means. The developed method is unique in simultaneous construction of indole structure and elongation of carbon scaffold.
  • 新規触媒開発によるカルボン酸の選択的活性化
    日本学術振興会：科学研究費補助金 研究活動スタート支援
    Date (from‐to) : 2011 -2013/03 
    Author : 清水洋平
  • Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research Grant-in-Aid for Research Activity start-up
    Date (from‐to) : 2011 -2012 
    Author : SHIMIZU Yohei
     
    We found that aldol reaction using carboxylic acids as substrates could be proceeded under mild condition by activating with an equivalent of borane. In addition, the usage of dummy ligands could tune the reactivity and selectivity.
  • Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research Grant-in-Aid for JSPS Fellows
    Date (from‐to) : 2008 -2010 
    Author : 清水 洋平
     
    天然に豊富に存在するグルコースやマンノースといった糖を求電子剤としピルビン酸誘導体を求核剤とした反応の開発を行った。求電子剤となる糖は酸性プロトンを有するヒドロキシル基が多数存在するため通常は保護を行う必要があるが、このような保護基の脱着なしに求核剤が糖を攻撃できる反応を開発できれば、糖を求電子剤とした系に限らず多くの天然物をより効率的に合成できる。それは複雑な縮環系に多くの官能基を有する化合物にも応用できると期待される。目的とする反応を達成するために、まずピルビン酸誘導体を求核剤として選択した。本基質は比較的高い酸性度を有していることから容易に求核的性質を有するエノール型をとると考えられ、さらに糖への付加が進行して得られる化合物はシアル酸であるため、生成物のさらなる修飾により様々な生物活性を有する化合物へと変換できると期待される。糖を求電子剤として様々な金属源を検討したが、その水溶性の高さゆえに取り扱い、分析が困難であったため、初期検討としてラクトールをモデル基質として再び触媒系を検討した。ラクトールはフリーのヒドロキシル基を有しており、また反応点となるアルデヒドがヘミアセタールとして保護された形も糖と類似しているため良いモデル基質となると考えた。ラクトールを用いた検討の結果Fe(III)を用いることで望みとする反応が良好に進行することが明らかとなった。中でもFe(CF_3CO_2)_3が最も良い結果を与えた。マンノースを求電子剤として用いた場合には反応は進行しなかったため、さらなる触媒系の検討を行っている。

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