有機触媒を用いたドミノ反応によるキラル有用化合物の迅速合成

• Project Area: Hybrid Catalysis for Enabling Molecular Synthesis on Demand
• Project/Area Number: 20H04801
• Research Category: Grant-in-Aid for Scientific Research on Innovative Areas (Research in a proposed research area)
• Allocation Type: Single-year Grants
• Review Section: Science and Engineering
• Research Institution: Tohoku University
• Principal Investigator: 林 雄二郎 東北大学, 理学研究科, 教授 (00198863)
• Project Period (FY): 2020-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥7,800,000 (Direct Cost: ¥6,000,000、Indirect Cost: ¥1,800,000); Fiscal Year 2021: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000); Fiscal Year 2020: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000)
• Keywords: ドミノ反応 / 有機触媒 / 不斉合成

Outline of Research at the Start

ドミノ反応は環境調和型の反応として注目を集めている。既に、２つのアミン触媒を合わせ用いるハイブリッド型触媒により、困難とされていたケトン／不飽和アルデヒド間の不斉触媒マイケル反応を見出している。この知見を発展させ、有機触媒を用いた不斉マイケル反応とドミノ反応を組み合わせる事により、重要な光学活性合成中間体を、環調和型手法で効率的に合成する事を目的とする。また開発した手法を、強力な生物活性を有する天然物の全合成に応用する。具体的には不斉触媒3+2付加環化反応を開発し、光学活性シクロペンタノンの合成法を確立する。それを利用したCorey lactoneの新規合成法の開発を行う。

Outline of Annual Research Achievements

ドミノ反応は同一容器内で複数の反応を順次行うために、中間体を単離する必要がなく、反応間における精製工程を省略するので、操作時間の短縮、廃溶媒の低減といった利点を有する環境調和型の反応である。これまでの研究で、２つのアミン触媒を合わせ用いるハイブリッド型触媒により、従来困難とされていたケトン／不飽和アルデヒド間の不斉触媒マイケル反応が高い不斉収率で進行することを見出している。今回、この知見をさらに発展させ、有機触媒を用いた不斉触媒反応と連続する反応を組み合わせたドミノ反応により、重要な光学活性合成中間体を、環調和型手法で効率的に合成した。
具体的にはアルキニルメチルケトンが優れたマイケル反応の求核剤となることを明らかにし、この反応を利用して高コレステロール治療薬であるリピトールの鍵中間体の不斉合成を達成した。
我々の開発した有機触媒存在下、isopropylidenemalononitrileとα,β不飽和アルデヒドを混合すると不斉触媒マイケル反応、分子内アルドール型反応が連続的に進行し、シクロヘキセン誘導体が高い光学純度で得られることを見出した。また、連続的不斉触媒マイケル反応、アルドール反応により、9メチルデカリンの光学活性体の合成にも成功した。さらに不斉触媒マイケル反応と分子内マイケル反応を連続的に進行させることにより光学活性ビシクロ[2.2.2]オクタン骨格、また置換シクロヘキサンを不斉合成した。これら得られた化合物は天然物合成の際の有用な合成中間体である。
このように、有機触媒を用いた不斉触媒反応と連続する反応を同一容器内で行うドミノ反応により、複数の結合を形成させ、一挙に複雑な骨格を有する分子の不斉合成に成功した。

Research Progress Status

令和3年度が最終年度であるため、記入しない。

Strategy for Future Research Activity

令和3年度が最終年度であるため、記入しない。

Research Products

• [Journal Article] Catalytic Asymmetric Michael Reaction of Methyl Alkynyl Ketone Catalyzed by Diphenylprolinol Silyl Ether (2022)
  • Author(s): Umekubo Nariyoshi、Hayashi Yujiro
  • Journal Title: ACS Organic & Inorganic Au Volume: 2 Issue: 3 Pages: 245-251
  • DOI: 10.1021/acsorginorgau.1c00054
  • Peer Reviewed
• [Journal Article] Asymmetric Michael Reaction of Malononitrile and α,β-Unsaturated Aldehydes Catalyzed by Diarylprolinol Silyl Ether (2022)
  • Author(s): Hayashi Yujiro、Hatano Yutaro、Mori Naoki
  • Journal Title: Synlett Volume: 33 Issue: 18 Pages: 1831-1836
  • DOI: 10.1055/a-1846-5007
  • Peer Reviewed
• [Journal Article] Diphenylprolinol Silyl Ether Catalyzed Asymmetric Formal Carbo [3+3] Cycloaddition Reaction of Isopropylidenemalononitrile and α,β‐Unsaturated Aldehyde (2022)
  • Author(s): Umekubo Nariyoshi、Han Xiaolei、Mori Naoki、Hayashi Yujiro
  • Journal Title: European Journal of Organic Chemistry Volume: 2022 Issue: 26
  • DOI: 10.1002/ejoc.202200603
  • Peer Reviewed
• [Journal Article] Asymmetric Synthesis of Functionalized 9-Methyldecalins Using a Diphenylprolinol-Silyl-Ether-Mediated Domino Michael/Aldol Reaction (2021)
  • Author(s): Hayashi Yujiro、Salazar Hugo A.、Koshino Seitaro
  • Journal Title: Organic Letters Volume: 23 Issue: 17 Pages: 6654-6658
  • DOI: 10.1021/acs.orglett.1c02196
  • Peer Reviewed
• [Journal Article] Enantiodivergent One‐Pot Synthesis of Axially Chiral Biaryls Using Organocatalyst‐Mediated Enantioselective Domino Reaction and Central‐to‐Axial Chirality Conversion (2021)
  • Author(s): Koshino Seitaro、Taniguchi Tohru、Monde Kenji、Kwon Eunsang、Hayashi Yujiro
  • Journal Title: Chemistry A European Journal Volume: 27 Issue: 63 Pages: 15786-15794
  • DOI: 10.1002/chem.202102797
  • Peer Reviewed
• [Journal Article] Synthesis of Bicyclo[2.2.2]octanes with a Quaternary Bridgehead Carbon by Diphenylprolinol Silyl Ether-mediated Domino Reaction (2021)
  • Author(s): Nariyoshi Umekubo, Tohru Taniguchi, Kenji Monde, Yujiro Hayashi
  • Journal Title: Asian J. Org. Chem. Volume: 10 Issue: 12 Pages: 3261-3265
  • DOI: 10.1002/ajoc.202100573
  • Peer Reviewed
• [Journal Article] Asymmetric Synthesis of Pentasubstituted Cyclohexanes through Diphenylprolinol Silyl Ether Mediated Domino Michael/Michael Reaction (2021)
  • Author(s): A. S. Odoh, L. Aidanpaa N. Umekubo, H. Matoba, N. Mori, Y. Hayashi
  • Journal Title: Eur. J. Org. Chem. Volume: なし Issue: 48 Pages: 6670-6673
  • DOI: 10.1002/ejoc.202101106
  • Peer Reviewed
• [Journal Article] Pot and time economies in the total synthesis of Corey lactone (2020)
  • Author(s): Nariyoshi Umekubo, Yurina Suga and Yujiro Hayashi
  • Journal Title: Chem. Sci. Volume: 10 Issue: 5 Pages: 1205-1209
  • DOI: 10.1039/c9sc05824a
  • Peer Reviewed / Open Access
• [Journal Article] Inversion of the axial information during oxidative aromatization in the synthesis of axially chiral biaryls using organocatalyst as a key step (2020)
  • Author(s): Koshino S., Takikawa A., Ishida K., Taniguchi T., Monde K., Kwon E., Umemiya S., Hayashi Y.
  • Journal Title: Chem. Eur. J. Volume: 26 Issue: 20 Pages: 4524-4530
  • DOI: 10.1002/chem.201905814
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Asymmetric Michael Reaction of Aldehydes and α‐Cyano α,β‐Unsaturated Esters Catalyzed by Diphenylprolinol Silyl Ether; a Facile Asymmetric Route to 3,4,5‐Trisubstituted Piperidines (2020)
  • Author(s): Hayashi Yujiro、Odoh Amaechi Shedrack、Kranidiotis‐Hisatomi Nektarios
  • Journal Title: ChemCatChem Volume: 12 Issue: 9 Pages: 2412-2415
  • DOI: 10.1002/cctc.202000113
  • Peer Reviewed
• [Journal Article] One-pot Synthesis of Chiral cis-Hydrindanes via Diphenylprolinol Silyl Ether Mediated Domino Reaction and Aldol Condensation (2020)
  • Author(s): Umekubo Nariyoshi、Iwata Ryohei、Hayashi Yujiro
  • Journal Title: Chemistry Letters Volume: 49 Issue: 7 Pages: 867-869
  • DOI: 10.1246/cl.200297
  • NAID: 130007872496
  • Peer Reviewed
• [Journal Article] Highly Enantioselective Access to syn-α,γ-Dihydroxycarbonyl Building Blocks via Organocatalyst-mediated Aldol Reaction as a Key Step (2020)
  • Author(s): Hayashi Yujiro、Wang Xiaoling、Kawauchi Genki
  • Journal Title: Chemistry Letters Volume: 49 Issue: 8 Pages: 940-943
  • DOI: 10.1246/cl.200304
  • NAID: 130007884739
  • Peer Reviewed
• [Journal Article] Asymmetric One‐Pot Mukaiyama Michael/Michael Reaction Catalyzed by Diphenylprolinol Silyl Ether (2020)
  • Author(s): Umekubo Nariyoshi、Hayashi Yujiro
  • Journal Title: European Journal of Organic Chemistry Volume: 2020 Issue: 34 Pages: 5596-5600
  • DOI: 10.1002/ejoc.202000925
  • Peer Reviewed
• [Journal Article] Asymmetric Synthesis of Corey Lactone and Latanoprost (2020)
  • Author(s): Umekubo Nariyoshi、Hayashi Yujiro
  • Journal Title: European Journal of Organic Chemistry Volume: 2020 Issue: 39 Pages: 6221-6227
  • DOI: 10.1002/ejoc.202001063
  • Peer Reviewed
• [Journal Article] Evidence for an enolate mechanism in the asymmetric Michael reaction of α,β-unsaturated aldehydes and ketones via a hybrid system of two secondary amine catalysts (2020)
  • Author(s): Umekubo Nariyoshi、Terunuma Takahiro、Kwon Eunsang、Hayashi Yujiro
  • Journal Title: Chemical Science Volume: 11 Issue: 41 Pages: 11293-11297
  • DOI: 10.1039/d0sc03359f
  • Peer Reviewed / Open Access
• [Journal Article] Asymmetric Domino Reaction of α,β-Unsaturated Aldehydes and α-Acyl α,β-Unsaturated Cyclic Ketones Catalyzed by Diphenylprolinol Silyl Ether (2020)
  • Author(s): Hayashi Yujiro、Suga Yurina、Umekubo Nariyoshi
  • Journal Title: Organic Letters Volume: 22 Issue: 21 Pages: 8603-8607
  • DOI: 10.1021/acs.orglett.0c03190
  • Peer Reviewed
• [Journal Article] Pot-Economical Total Synthesis of Clinprost (2020)
  • Author(s): Umekubo Nariyoshi、Hayashi Yujiro
  • Journal Title: Organic Letters Volume: 22 Issue: 23 Pages: 9365-9370
  • DOI: 10.1021/acs.orglett.0c03616
  • Peer Reviewed
• [Presentation] Pot-Economical Total Synthesis of (－)-Quinine Using Organocatalyst (2022)
  • Author(s): Takahito Terunuma, Yujiro Hayashi
  • Organizer: 日本化学会第102春季年会
• [Presentation] Efficiency in the synthesis of biologically active molecules (2022)
  • Author(s): Yujiro Hayashi
  • Organizer: 2022 12th International Conference on Chemistry and Chemical Process (ICCCP 2022)
  • Invited
• [Presentation] 有機触媒を用いた(－)-キニーネの効率的不斉全合成 (2021)
  • Author(s): Terunuma, Yujiro Hayashi
  • Organizer: 天然物化学討論会
• [Presentation] Asymmetric Michael reaction of malononitrile to a,b-unsaturated aldehydecatalyzed by organocatalyst (2021)
  • Author(s): Yutaro Hatano, Naoki Mori, Yujiro Hayashi
  • Organizer: 日本化学会東北支部化学系学協会東北大会
• [Presentation] Asymmetric synthesis of noradamantane scaffolds using diphenylprolinol silyl ether-mediated domino reaction (2021)
  • Author(s): Konstantinos Daskalakis, Nariyoshi Umekubo, Yujiro Hayashi
  • Organizer: 第14回 有機触媒シンポジウム
• [Presentation] 有機触媒とフッ素化学 (2021)
  • Author(s): 林 雄二郎
  • Organizer: 相模フッ素セミナー、相模中央化学研究所主宰
  • Invited
• [Presentation] ポットエコノミー、タイムエコノミーを志向した全合成 (2021)
  • Author(s): 林 雄二郎
  • Organizer: 第52回中部化学関係学協会支部連合（中化連）秋季大会特別討論会
  • Invited
• [Presentation] Pot Economy in Total Synthesis (2021)
  • Author(s): Yujiro Hayashi
  • Organizer: World Class Professor 2021, (on line) Universitas Gadjah Mada, Indonesia and Institut des Sciences Moleculaires de Marseille, France
  • Invited
• [Presentation] Time and pot economical synthesis of biologically active molecules using organocatalyst (2021)
  • Author(s): Yujiro Hayashi
  • Organizer: 2021 International Chemical Congress of Pacific Basin Societies (PACIFICHEM 2021)
  • Invited
• [Presentation] Recent development of asymmetric catalytic reactions using diphenylprolinol silyl ether as a catalyst (2021)
  • Author(s): Yujiro Hayashi
  • Organizer: 2021 International Chemical Congress of Pacific Basin Societies (PACIFICHEM 2021)
  • Invited
• [Presentation] Synthetic Study of a Polyol Unit of Amphotericin B Using Organocatalysts (2021)
  • Author(s): Genki Kawauchi, Yujiro Hayashi
  • Organizer: 日本化学会第101春季年会、オンライン開催
• [Presentation] Synthetic study on morphine using hydrogen atom transfer reaction to construct asymmetric quaternary carbon (2021)
  • Author(s): Naoki Mori, Yujiro Hayashi
  • Organizer: 日本化学会第101春季年会、オンライン開催
• [Presentation] Pot-Economical Synthesis of Prostaglandins (2021)
  • Author(s): Nariyoshi Umekubo, Yujiro Hayashi
  • Organizer: 日本化学会第101春季年会、オンライン開催
• [Presentation] Peptide ligation between α-amidonitrile and N-terminal cysteine (2021)
  • Author(s): Xiaoling Wang, Jing Li, Yujiro Hayashi
  • Organizer: 日本化学会第101春季年会、オンライン開催
• [Presentation] Stereoselective synthesis of chiral anti-1,3-diols using diastereoselective epoxidation (2021)
  • Author(s): Masashi Tomikawa, Mori Naoki, Yujiro Hayashi
  • Organizer: 日本化学会第101春季年会、オンライン開催
• [Presentation] Amphiphilic immobilized diphenylprolinol alkyl ether catalyst on PS-PEG resin (2021)
  • Author(s): Shusuke Hattori, Seitaro Koshino, Yasuhiro Uozumi, Yujiro Hayashi
  • Organizer: 日本化学会第101春季年会、オンライン開催
• [Presentation] Asymmetric synthesis of tri-substituted cis-hydrindanes via organocatalyst-mediated domino Michael/Michael reactio (2021)
  • Author(s): Ryohei Iwata, Nariyoshi Umekubo, Yujiro Hayashi
  • Organizer: 日本化学会第101春季年会、オンライン開催
• [Presentation] Asymmetric Michael reaction of a,b-unsaturated aldehyde and malononitrile catalyzed by organocatalyst (2021)
  • Author(s): Yutaro Hatano, Naoki Mori, Yujiro Hayashi
  • Organizer: 日本化学会第101春季年会、オンライン開催
• [Presentation] One-pot enantiodivergent synthesis of axially chiral biaryls using organocatalyst (2021)
  • Author(s): Seitaro Koshino, Tohru Taniguchi, Kenji Monde, Eunsang Kwon, Yujiro Hayashi
  • Organizer: 日本化学会第101春季年会、オンライン開催
• [Presentation] Time and Pot Economy in Total Synthesis (2021)
  • Author(s): Yujiro Hayashi
  • Organizer: 2021 8th International Conference on Chemical and Biological Sciences (ICCBS 2021), 2021 11th International Conference on Chemistry and Chemical Process (ICCCP 2021)
  • Int'l Joint Research / Invited
• [Presentation] ポットエコノミーを指向したプロスタグランジン類の効率的合成 (2020)
  • Author(s): 楳窪成祥, 林雄二郎
  • Organizer: 第62回天然物討論会, オンライン学会
• [Presentation] Amphiphilic immobilized diphenylprolinol alkyl ether (2020)
  • Author(s): Shusuke Hattori, Seitaro Koshino, Yasuhiro Uozumi, Yujiro Hayashi
  • Organizer: 令和 2 年度化学系学協会東北大会, オンライン開催
• [Presentation] Synthesis of chiral anti β, δ-dihydroxy ester using organocatalyst mediated reaction as a key step (2020)
  • Author(s): Masashi Tomikawa, Mori Naoki, Yujiro Hayashi
  • Organizer: 令和 2 年度化学系学協会東北大会, オンライン開催
• [Presentation] Asymmetric vinylogous Mihcael reaction of α, β-unsaturated aldehyde andcyclic α-acyl α, β-unsaturated ketone catalyzed by diphenyl prolinol silyl ether (2020)
  • Author(s): Yurina Suga, Nariyoshi Umekubo, Yujiro Hayashi
  • Organizer: 令和 2 年度化学系学協会東北大会, オンライン開催
• [Presentation] 高分子担持型ジフェニルプロリノールアルキルエーテルの開発 (2020)
  • Author(s): Shusuke Hattori, Seitaro Koshino, Yasuhiro Uozumi, Yujiro Hayashi
  • Organizer: 第31回万有仙台シンポジウム, オンライン開催
• [Presentation] 実用的有機触媒反応の開発および生物活性化合物の短工程合成への展開 (2020)
  • Author(s): 林 雄二郎
  • Organizer: 第62回有機合成化学協会 協会賞受賞講演、有機合成化学協会、如水会館、東京
  • Invited
• [Presentation] Time Economy in Total Synthesis (2020)
  • Author(s): Yujiro Hayashi
  • Organizer: 7th Annual Convertion of Chemists (ACC), Indian Chemical Society (ICS), Organic & Bio-Chemistry Section, IISER Kolkata, India (on line) (plenary)
  • Int'l Joint Research / Invited