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Development of asymmetric dehydration condensation reaction with kinetic or dynamic kinetic resolution of enantiomers and effective synthesis of non-natural amino acids

Research Project

Project/Area Number 17H03024
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field Organic chemistry
Research InstitutionTokyo University of Science

Principal Investigator

Shiina Isamu  東京理科大学, 理学部第一部応用化学科, 教授 (40246690)

Co-Investigator(Kenkyū-buntansha) 中田 健也  島根大学, 学術研究院環境システム科学系, 准教授 (00434019)
Project Period (FY) 2017-04-01 – 2021-03-31
Project Status Completed (Fiscal Year 2020)
Budget Amount *help
¥18,590,000 (Direct Cost: ¥14,300,000、Indirect Cost: ¥4,290,000)
Fiscal Year 2020: ¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000)
Fiscal Year 2019: ¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000)
Fiscal Year 2018: ¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000)
Fiscal Year 2017: ¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000)
Keywords有機合成化学 / 速度論的光学分割 / 動的速度論光学分割 / 全合成
Outline of Final Research Achievements

Using our kinetic resolution method of 2-hydroxypropanoic acid esters and the dynamic kinetic resolution method with racemization of the starting materials, we designed a new method for producing optically active esters that surpasses the enzymatic reaction.
In these subjects, we took up racemic secondary alcohols, 2-substituted propanoic esters, and α-amino acids, etc. as substrates for giving optically active substances in high yields using the enantioselective organic synthetic methodologies.
Through the promotion of this subject, we developed an effective method for synthesizing chiral carboxylic acids and related compounds, which are highly versatile and have excellent substrate generality. Furthermore, we accomplished the total synthesis of pharmacologically active compounds which have not been feasible until now.

Academic Significance and Societal Importance of the Research Achievements

我々が独自に開発したKR法およびDKR法を鍵工程として用いることで、学術的ならび社会的に求められている光学活性な特殊アミノ酸ならびに薬理活性化合物の合成手段を確立することに成功した。一つの例として、非天然型アミノ酸であり需要の高い(S)-および(R)-2-アリールグリシン混合物のDKRを試みたところ高エナンチオ選択的に不斉エステル化が進行し、目的とする光学活性エステルを得ることができた。さらに、ラセミ多置換2-アリールプロピオン酸のDKRを利用することで、光学純度の高いドラグマシジンD合成中間体の簡便な供給法を見出すことに成功し、抗腫瘍活性化合物ドラグマシジンDの形式不斉全合成を達成した。

Report

(3 results)
  • 2020 Final Research Report ( PDF )
  • 2019 Annual Research Report
  • 2018 Annual Research Report
  • Research Products

    (29 results)

All 2020 2019 2018 2017 Other

All Journal Article (22 results) (of which Int'l Joint Research: 2 results,  Peer Reviewed: 21 results,  Open Access: 5 results) Presentation (4 results) Book (1 results) Remarks (1 results) Patent(Industrial Property Rights) (1 results) (of which Overseas: 1 results)

  • [Journal Article] Kinetic Resolution of Racemic 2‐Hydroxyarylketones by Asymmetric Esterification: Investigation of the Influence of the Co‐Base on the Selectivity2020

    • Author(s)
      Murata Takatsugu、Futami Kengo、Ishikawa Ryo、Ono Keisuke、Nakata Kenya、Shiina Isamu
    • Journal Title

      Asian Journal of Organic Chemistry

      Volume: 9 Issue: 2 Pages: 202-205

    • DOI

      10.1002/ajoc.201900702

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Total Synthesis of the Antitumor Depsipeptide FE399 and its S-Benzyl Derivative: A Macrolactamization Approach2020

    • Author(s)
      Tonoi Takayuki、Ikeda Miyuki、Sato Teruyuki、Inohana Takehiko、Kawahara Ryo、Murata Takatsugu、Shiina Isamu
    • Journal Title

      ChemRxiv

      Volume: 4 Pages: 1-16

    • DOI

      10.26434/chemrxiv.12017796

    • Related Report
      2019 Annual Research Report
    • Open Access
  • [Journal Article] Novel Ridaifen-B Structure Analog Induces Apoptosis and Autophagy Depending on Pyrrolidine Side Chain2019

    • Author(s)
      Iwasawa Takumi、Shinomiya Takahisa、Ota Nozomi、Shibata Natsumi、Nakata Kenya、Shiina Isamu、Nagahara Yukitoshi
    • Journal Title

      Biological and Pharmaceutical Bulletin

      Volume: 42 Issue: 3 Pages: 401-410

    • DOI

      10.1248/bpb.b18-00643

    • NAID

      130007605974

    • ISSN
      0918-6158, 1347-5215
    • Year and Date
      2019-03-01
    • Related Report
      2019 Annual Research Report 2018 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Diastereo-/Enantioselective Diels-Alder Synthesis of 14β-Hydroxysteroid Scaffolds: A Combined Experimental and DFT Study2019

    • Author(s)
      Shiina Isamu、Miesch Michel、Peter Clovis、Geoffroy Philippe、Murata Takatsugu、Tonoi Takayuki
    • Journal Title

      HETEROCYCLES

      Volume: 99 Issue: 2 Pages: 1251-1251

    • DOI

      10.3987/com-18-s(f)99

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] N822K-or V560G-mutated KIT activation preferentially occurs in lipid rafts of the Golgi apparatus in leukemia cells2019

    • Author(s)
      Obata Y, Hara Y, Shiina I, Murata T, Tasaki Y, Suzuki K, Ito K, Tsugawa S, Yamawaki K, Takahashi T, Okamoto K, Nishida T, Abe R.
    • Journal Title

      Cell Commun. Signal.

      Volume: 17 Issue: 1 Pages: 114-114

    • DOI

      10.1186/s12964-019-0426-3

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Total Synthesis and Antimicrobial Evaluation of 23-Demethyleushearilide and Extensive Antimicrobial Evaluation of All Synthetic Stereoisomers of (16Z,20E)-Eushearilide and (16E,20E)-Eushearilide2019

    • Author(s)
      Tonoi Takayuki、Inohana Takehiko、Sato Teruyuki、Noda Yuuki、Ikeda Miyuki、Akutsu Miku、Murata Takatsugu、Maekawa Yutaro、Tanaka Anna、Seki Rio、Ohkusu Misako、Kamei Katsuhiko、Ishiwada Naruhiko、Shiina Isamu
    • Journal Title

      Molecules

      Volume: 24 Issue: 19 Pages: 3437-3437

    • DOI

      10.3390/molecules24193437

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Chiral-Auxiliary-Controlled Diastereoconvergent Benzamidation Reactions of Diastereomixtures of Diarylmethanols with Benzamide Catalyzed by SnBr42019

    • Author(s)
      Kubo Rikiya、Nakata Kenya
    • Journal Title

      Asian Journal of Organic Chemistry

      Volume: 8 Issue: 1 Pages: 119-122

    • DOI

      10.1002/ajoc.201800635

    • Related Report
      2019 Annual Research Report 2018 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Reformatsky Reagent Promoted Acetylation of Primary and Secondary Aliphatic Alcohols Using Ethyl Acetate as an Acetyl Donor2019

    • Author(s)
      Fujihara Rina、Nakata Kenya
    • Journal Title

      ChemistrySelect

      Volume: 4 Issue: 1 Pages: 75-77

    • DOI

      10.1002/slct.201803162

    • Related Report
      2019 Annual Research Report 2018 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Diastereoconvergent Synthesis of Chiral Diarylmethyl Sulfones by Direct Sulfonylation of Diarylmethanols Diastereomixtures with Sodium Sulfinates Catalyzed by SnBr22019

    • Author(s)
      Yamamoto Hiroshi、Nakata Kenya
    • Journal Title

      European Journal of Organic Chemistry

      Volume: 2019 Issue: 30 Pages: 4906-4910

    • DOI

      10.1002/ejoc.201900830

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Acylative Kinetic Resolution of Racemic 2,2‐Dimethyl‐Substituted Nitroaldol (Henry) Adducts Using a Chiral Guanidine Catalyst: (R)‐(+)‐N‐Methylbenzoguanidine ((R)‐NMBG)2019

    • Author(s)
      Ichimura Taiju、Kishida Ryota、Nakata Kenya
    • Journal Title

      ChemistrySelect

      Volume: 4 Issue: 32 Pages: 9440-9443

    • DOI

      10.1002/slct.201902236

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Silylative Kinetic Resolution of Racemic 2,2‐Dialkyl 5‐ and 6‐Membered Cyclic Benzylic Alcohol Derivatives Catalyzed by Chiral Guanidine, (R)‐N‐Methylbenzoguanidine2019

    • Author(s)
      Yoshimatsu Shuhei、Nakata Kenya
    • Journal Title

      Advanced Synthesis & Catalysis

      Volume: 361 Issue: 20 Pages: 4679-4684

    • DOI

      10.1002/adsc.201900761

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Diastereoconvergent Dehydrative Nucleophilic Substitutions of Diastereomeric Diarylmethanols with 1,3-Dicarbonyls Catalyzed by SnBr42019

    • Author(s)
      Kubo Rikiya、Yamamoto Hiroshi、Nakata Kenya
    • Journal Title

      European Journal of Organic Chemistry

      Volume: 2019 Issue: 44 Pages: 7394-7398

    • DOI

      10.1002/ejoc.201901377

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Asymmetric Total Synthesis of (+)-Coprophilin2018

    • Author(s)
      Shiina Isamu、Umezaki Yuma、Murata Takatsugu、Suzuki Kyohei、Tonoi Takayuki
    • Journal Title

      Synthesis

      Volume: 50 Issue: 06 Pages: 1301-1306

    • DOI

      10.1055/s-0036-1591866

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Oncogenic Kit signalling on the Golgi is suppressed by blocking secretory trafficking with M-COPA in gastrointestinal stromal tumours.2018

    • Author(s)
      Obata Y, Horikawa K, Shiina I, Takahashi T, Murata T, Tasaki Y, Suzuki K, Yonekura K, Esumi H, Nishida T, Abe R
    • Journal Title

      Cancer Lett.

      Volume: 415 Pages: 1-10

    • DOI

      10.1016/j.canlet.2017.11.032

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Ridaifen-F conjugated with cell-penetrating peptides inhibits intracellular proteasome activities and induces drug-resistant cell death.2018

    • Author(s)
      Tanaka, M., Zhu, Y., Shionyu, M., Ota, N., Shibata, N., Watanabe, C., Mizusawa, A., Sasaki, R., Mizukami, T., Shiina, I., Hasegawa, M.
    • Journal Title

      European Journal of Medicinal Chemistry

      Volume: 146 Pages: 636-650

    • DOI

      10.1016/j.ejmech.2018.01.045

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Total Synthesis and Antimicrobial Activities of All Stereoisomers of (16Z,20E)-Eushearilide and (16E,20E)-Eushearilide2018

    • Author(s)
      Tonoi Takayuki、Inohana Takehiko、Sato Teruyuki、Yoshida Tomoki、Shiina Isamu
    • Journal Title

      The Journal of Organic Chemistry

      Volume: 83 Issue: 15 Pages: 7886-7899

    • DOI

      10.1021/acs.joc.8b00774

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Anti-proliferative effect of ridaifen-B on hepatoma cells2018

    • Author(s)
      Hasegawa Go、Akatsuka Kotomi、Hiruma Keita、Suda Kayako、Yokoe Yumiko、Mizusawa Akihito、Ota Nozomi、Shibata Natsumi、Tsuchiya Kaho、Hayashi Moyuru、Shiina Isamu、Shimonaka Motoyuki
    • Journal Title

      Biomedical Reports

      Volume: 9 Pages: 175-180

    • DOI

      10.3892/br.2018.1112

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Kinetic Resolution of Racemic 2-Hydroxyamides Using a Diphenylacetyl Component as an Acyl Source and a Chiral Acyl-Transfer Catalyst2018

    • Author(s)
      Murata Takatsugu、Kawanishi Tatsuya、Sekiguchi Akihiro、Ishikawa Ryo、Ono Keisuke、Nakata Kenya、Shiina Isamu
    • Journal Title

      Molecules

      Volume: 23 Issue: 8 Pages: 2003-2021

    • DOI

      10.3390/molecules23082003

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Total Synthesis of Violaceoid A and (-)- and (+)-Violaceoid B2018

    • Author(s)
      Murata Takatsugu、Kuboki Teppei、Ishikawa Ryo、Saito Takahiro、Taguchi Shotaro、Takeuchi Kazuma、Hatano Emiko、Shimonaka Motoyuki、Shiina Isamu
    • Journal Title

      Journal of Natural Products

      Volume: 81 Issue: 11 Pages: 2364-2370

    • DOI

      10.1021/acs.jnatprod.8b00215

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Chiral Inductive Diastereoconvergent Allylation Reactions of Allyltrimethylsilane and Diastereomixtures of Diarylmethanols Catalyzed by FeCl32018

    • Author(s)
      Fujihara Rina、Nakata Kenya
    • Journal Title

      European Journal of Organic Chemistry

      Volume: 2018 Issue: 46 Pages: 6566-6573

    • DOI

      10.1002/ejoc.201801236

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Stereoconvergent Chiral Inductive Diastereodivergent Sulfonamidation of Diastereomixtures of Diarylmethanols with Sulfonylamine Catalyzed by Lewis Acids2018

    • Author(s)
      Yamamoto Hiroshi、Nakata Kenya
    • Journal Title

      Organic Letters

      Volume: 20 Issue: 22 Pages: 7057-7061

    • DOI

      10.1021/acs.orglett.8b03008

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Targeting the Golgi apparatus to overcome acquired resistance of non-small cell lung cancer cells to EGFR tyrosine kinase inhibitors2017

    • Author(s)
      Yoshimi Ohashi, Mutsumi Okamura, Ryohei Katayama, Siyang Fang, Saki Tsutsui, Akinobu Akatsuka, Mingde Shan, Hyeong-Wook Choi, Naoya Fujita, Kentaro Yoshimatsu, Isamu Shiina, Takao Yamori, and Shingo Dan
    • Journal Title

      Oncotarget

      Volume: 9 Issue: 2 Pages: 1641-1655

    • DOI

      10.18632/oncotarget.22895

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Presentation] 不斉エステル化反応を用いたラセミ2-ヒドロキシ(アリール)ケトン類の速度論的光学分割ならびに遷移構造解析2020

    • Author(s)
      村田 貴嗣、中田 健也、椎名 勇
    • Organizer
      日本化学会第100春季年会
    • Related Report
      2019 Annual Research Report
  • [Presentation] 二置換ナフタレン構造を有するジプロピオン酸を用いた動的速度論的光学分割法の開発2020

    • Author(s)
      村田 貴嗣、高間 愛実、中田 健也、椎名 勇
    • Organizer
      日本化学会第100春季年会
    • Related Report
      2019 Annual Research Report
  • [Presentation] アリールジプロピオン酸類の動的速度論的光学分割法の開発研究2019

    • Author(s)
      村田貴嗣、高間愛実、中田健也、椎名 勇
    • Organizer
      日本化学会第99春季年会
    • Related Report
      2018 Annual Research Report
  • [Presentation] MNBAを用いるω-アミノカルボン酸のマクロラクタム化反応2019

    • Author(s)
      椎名 勇、野田有希、殿井貴之
    • Organizer
      日本化学会第99春季年会
    • Related Report
      2018 Annual Research Report
  • [Book] エステル・アミドって何? ラクトンって何? -理科大発! MNBAを用いた世界最速合成法の開発-2019

    • Author(s)
      椎名 勇
    • Total Pages
      6
    • Publisher
      理大科学フォーラム
    • Related Report
      2019 Annual Research Report
  • [Remarks] 有機合成で「脱水」する! ー高速脱水縮合剤MNBAのはたらきー

    • URL

      https://www.youtube.com/watch?v=vC_GaybLBNo

    • Related Report
      2018 Annual Research Report
  • [Patent(Industrial Property Rights)] 安息香酸誘導体及び脱水縮合剤、並びにエステル及びラクトンの製造方法2018

    • Inventor(s)
      椎名 勇
    • Industrial Property Rights Holder
      椎名 勇
    • Industrial Property Rights Type
      特許
    • Filing Date
      2018
    • Related Report
      2018 Annual Research Report
    • Overseas

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Published: 2017-04-28   Modified: 2023-12-25  

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