理論計算を基盤とした生合成経路の探索と生合成リデザインへの挑戦

• Project Area: Creation of Complex Functional Molecules by Rational Redesign of Biosynthetic Machineries
• Project/Area Number: 19H04643
• 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: The University of Tokyo
• Principal Investigator: 内山 真伸 東京大学, 大学院薬学系研究科(薬学部), 教授 (00271916)
• Project Period (FY): 2019-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥7,800,000 (Direct Cost: ¥6,000,000、Indirect Cost: ¥1,800,000); Fiscal Year 2020: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000); Fiscal Year 2019: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000)
• Keywords: 理論計算 / 生合成経路

Outline of Research at the Start

本研究では、まずジテルペン・セスタテルペン系天然物を取り上げ、反応経路自動探索法 (GRRM、ReactionPlus)などを駆使して、環化反応経路の網羅的全貌解析に取り組む。理論計算により取得した全ての中間体・遷移状態構造に対して NBO 計算を駆使した軌道解析を行い、反応駆動力の解明、カチオンの安定性、立体・化学選択性の定量的な評価を試みる。

Outline of Annual Research Achievements

多種多様な構造を持つテルペノイドは、テルペン環化酵素により基本骨格構築がされており、その反応機構の解明は分子多様性解明の鍵となる。しかしながら、酵素内部での複雑な連続多段階反応のため、中間体の単離や反応機構の全容解明は実験科学のみでは困難である。本研究では、異なる数種のテルペノイドの環化反応の計算科学・理論解析を通して構造多様性創出の原理(反応経路、選択性発現機構など)を明らかにし、実験化学者との共同研究を通じて遷移状態制御により新規セスタテルペン骨格構築への発展を目指し研究を行った。主な成果として、セスキテルペン化合物 Trichobrasilenol の生合成経路の解明について述べる。セスキテルペン類によく見られるbicyclo[4.3.0]nonane 構造は、「ブラシラン型骨格」と呼ばれ、40 年以上前に発見・報告されたにも関わらず、その生合成メカニズムはずっと謎のままであった。2020 年に本研究領域内の東京大学の葛山教授らにより、1,3-水素移動反応、3 箇所の CーC 結合の開裂、π結合の生成、水和反応という 6 個の化学反応が進行することが緻密な標識実験によって示されたが、この複雑骨格合成のための反応機構にはいくつかの疑問が残ったままであった。本研究では、我々が独自に開発した様々な理論的手法を駆使することで、ブラシラン型骨格の新たな生成メカニズムの提案に成功した。この反応機構は、標識実験の結果とも完全に合致し、また類縁体天然物の生合成も説明できる非常に合理的なものであった。他にも、セスタテルペン合成酵素の初期配座固定メカニズムの解明、Preasperterpenoid 類の反応機構解析、インドールジテルペン化合物 Lolitrem 生合成でのラジカル閉環反応の理論解析、海洋天然物シマラクトンにおける電子環状反応の理論解析にも成功した。

Research Progress Status

令和2年度が最終年度であるため、記入しない。

Strategy for Future Research Activity

令和2年度が最終年度であるため、記入しない。

Research Products

• [Journal Article] Nucleophilic Activation of Hydrosilanes via a Strain-Imposing Strategy Leading to Functional Sila-aromatics (2021)
  • Author(s): Ikeuchi Toshiya、Hirano Keiichi、Uchiyama Masanobu
  • Journal Title: Journal of the American Chemical Society Volume: 143 Issue: 13 Pages: 4879-4885
  • DOI: 10.1021/jacs.0c12619
  • Peer Reviewed
• [Journal Article] Illuminating Stannylation (2021)
  • Author(s): Sakamoto Kyoka、Nagashima Yuki、Wang Chao、Miyamoto Kazunori、Tanaka Ken、Uchiyama Masanobu
  • Journal Title: Journal of the American Chemical Society Volume: 143 Issue: 15 Pages: 5629-5635
  • DOI: 10.1021/jacs.1c00887
  • Peer Reviewed
• [Journal Article] α‐Cyclodextrin Encapsulation of Bicyclo[1.1.1]pentane Derivatives: A Storable Feedstock for Preparation of [1.1.1]Propellane (2021)
  • Author(s): Matsunaga Tadafumi、Kanazawa Junichiro、Ichikawa Tomohiro、Harada Mei、Nishiyama Yusuke、Duong Nghia Tuan、Matsumoto Takashi、Miyamoto Kazunori、Uchiyama Masanobu
  • Journal Title: Angewandte Chemie International Edition Volume: 60 Issue: 5 Pages: 2578-2582
  • DOI: 10.1002/anie.202014997
  • Peer Reviewed
• [Journal Article] Inter‐Element Boration Reactions of Carbon‐Carbon Multiple Bonds via Lewis‐Basic Activation of Boron Reagents (2021)
  • Author(s): Hirano Keiichi、Uchiyama Masanobu
  • Journal Title: Advanced Synthesis & Catalysis Volume: 363 Issue: 9 Pages: 2340-2353
  • DOI: 10.1002/adsc.202001610
  • Peer Reviewed
• [Journal Article] Development of Phthalocyanine-Based Functional Molecules with Tunable Optical and Chiroptical Properties (2021)
  • Author(s): Muranaka Atsuya、Uchiyama Masanobu
  • Journal Title: Bulletin of the Chemical Society of Japan Volume: 94 Issue: 3 Pages: 872-878
  • DOI: 10.1246/bcsj.20200336
  • NAID: 130008021849
  • Peer Reviewed / Open Access
• [Journal Article] Room-temperature Chemical Synthesis of C2 (2020)
  • Author(s): Kazunori Miyamoto, Shodai Narita, Yui Masumoto, Takahiro Hashishin, Taisei Osawa, Mutsumi Kimura, Masahito Ochiai, Masanobu Uchiyama
  • Journal Title: Nature Communcations Volume: 11 Issue: 1 Pages: 2134-2134
  • DOI: 10.1038/s41467-020-16025-x
  • Peer Reviewed / Open Access
• [Journal Article] DFT Study of a Missing Piece in Brasilane-Type Structure Biosynthesis: An Unusual Skeletal Rearrangement (2020)
  • Author(s): Sato Hajime、Hashishin Takahiro、Kanazawa Junichiro、Miyamoto Kazunori、Uchiyama Masanobu
  • Journal Title: Journal of the American Chemical Society Volume: 142 Issue: 47 Pages: 19830-19834
  • DOI: 10.1021/jacs.0c09616
  • Peer Reviewed
• [Journal Article] Nucleophilic Diboration Strategy Targeting Diversified 1‐Boraphenarene Architectures (2020)
  • Author(s): Hirano Keiichi、Morimoto Kensuke、Fujioka Shota、Miyamoto Kazunori、Muranaka Atsuya、Uchiyama Masanobu
  • Journal Title: Angewandte Chemie International Edition Volume: 59 Issue: 48 Pages: 21448-21453
  • DOI: 10.1002/anie.202009242
  • Peer Reviewed
• [Journal Article] Biosynthesis of Indole Diterpene Lolitrems: Radical-Induced Cyclization of an Epoxyalcohol Affording a Characteristic Lolitremane Skeleton (2020)
  • Author(s): Yulu Jiang, Taro Ozaki, Mei Harada, Tadachika Miyasaka, Hajime Sato, Kazunori Miyamoto, Junichiro Kanazawa, Chengwei Liu, Jun-ichi Maruyama, Masaatsu Adachi, Atsuo Nakazaki, Toshio Nishikawa, Masanobu Uchiyama, Atsushi Minami, Hideaki Oikawa
  • Journal Title: Angew. Chem. Int. Ed. Volume: 59 Issue: 41 Pages: 17996-18002
  • DOI: 10.1002/anie.202007280
  • NAID: 120007160289
  • Peer Reviewed
• [Journal Article] Sila‐ and Germacarboxylic Acids: Precursors for the Corresponding Silyl and Germyl Radicals (2020)
  • Author(s): Xu Ning‐Xin、Li Bi‐Xiao、Wang Chao、Uchiyama Masanobu
  • Journal Title: Angewandte Chemie International Edition Volume: 59 Issue: 26 Pages: 10639-10644
  • DOI: 10.1002/anie.202003070
  • Peer Reviewed
• [Journal Article] Decarboxylative Bromination of Sterically Hindered Carboxylic Acids with Hypervalent Iodine(III) Reagents (2020)
  • Author(s): Watanabe Ayumi、Koyamada Kenta、Miyamoto Kazunori、Kanazawa Junichiro、Uchiyama Masanobu
  • Journal Title: Organic Process Research & Development Volume: 24 Issue: 7 Pages: 1328-1334
  • DOI: 10.1021/acs.oprd.0c00130
  • Peer Reviewed
• [Journal Article] A remarkably air-stable quinodimethane radical cation (2020)
  • Author(s): Harada Mei、Tanioka Masaru、Muranaka Atsuya、Aoyama Tetsuya、Kamino Shinichiro、Uchiyama Masanobu
  • Journal Title: Chemical Communications Volume: 56 Issue: 66 Pages: 9565-9568
  • DOI: 10.1039/d0cc04025h
  • Peer Reviewed
• [Journal Article] Silaboration of [1.1.1]Propellane: A Storable Feedstock for Bicyclo[1.1.1]pentane Derivatives (2020)
  • Author(s): Kondo Masaki、Kanazawa Junichiro、Ichikawa Tomohiro、Shimokawa Takumi、Nagashima Yuki、Miyamoto Kazunori、Uchiyama Masanobu
  • Journal Title: Angewandte Chemie International Edition Volume: 59 Issue: 5 Pages: 1970-1974
  • DOI: 10.1002/anie.201909655
  • Peer Reviewed
• [Journal Article] Ring‐Opened Hemiporphyrazines: Helical Molecules Exhibiting Circularly Polarized Luminescence (2020)
  • Author(s): Tanaka Yusuke、Murayama Tomotaka、Muranaka Atsuya、Imai Eiyu、Uchiyama Masanobu
  • Journal Title: Chemistry A European Journal Volume: 26 Issue: 8 Pages: 1768-1771
  • DOI: 10.1002/chem.201905246
  • Peer Reviewed
• [Journal Article] Lipshutz-type Bis(amido)argentate for Directed ortho Argentation (2020)
  • Author(s): Noriyuki Tezuka, Keiichi Hirano, Andrew J. Peel, Andrew E. H. Wheatley, Kazunori Miyamoto, Masanobu Uchiyama
  • Journal Title: Chemical Sciences Volume: 11 Issue: 7 Pages: 1855-1861
  • DOI: 10.1039/c9sc06060j
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Diaryl-λ3-chloranes: Versatile Synthesis and Unique Reactivity as Aryl Cation Equivalent (2019)
  • Author(s): Nakajima Misuzu、Miyamoto Kazunori、Hirano Keiichi、Uchiyama Masanobu
  • Journal Title: Journal of the American Chemical Society Volume: 141 Issue: 16 Pages: 6499-6503
  • DOI: 10.1021/jacs.9b02436
  • Peer Reviewed
• [Journal Article] Quadruple Borylation of Terminal Alkynes (2019)
  • Author(s): Daiki Yukimori, Yuki Nagashima, Chao Wang, Atsuya Muranaka, and Masanobu Uchiyama
  • Journal Title: J. Am. Chem. Soc. Volume: 141 Issue: 25 Pages: 9819-9822
  • DOI: 10.1021/jacs.9b04665
  • Peer Reviewed
• [Journal Article] Design of Photostable, Activatable Near‐Infrared Photoacoustic Probes Using Tautomeric Benziphthalocyanine as a Platform (2019)
  • Author(s): Naoyuki Toriumi, Norihito Asano, Takayuki Ikeno, Atsuya Muranaka, Kenjiro Hanaoka, Yasuteru Urano, Masanobu Uchiyama
  • Journal Title: Angew. Chem. Int. Ed. Volume: 58 Issue: 23 Pages: 7788-7791
  • DOI: 10.1002/anie.201903303
  • Peer Reviewed
• [Journal Article] Alkynylboration Reaction Leading to Boron-Containing π-Extended cis-Stilbenes as a Highly Tunable Fluorophore (2019)
  • Author(s): Nogami Marina、Hirano Keiichi、Morimoto Kensuke、Tanioka Masaru、Miyamoto Kazunori、Muranaka Atsuya、Uchiyama Masanobu
  • Journal Title: Organic Letters Volume: 21 Issue: 9 Pages: 3392-3395
  • DOI: 10.1021/acs.orglett.9b01132
  • Peer Reviewed
• [Journal Article] A Direct, Chemo-, and Regioselective Cross-Coupling Reaction of Arenes via Sequential Directed ortho Cuprations and Oxidation (2019)
  • Author(s): Tezuka Noriyuki、Hirano Keiichi、Uchiyama Masanobu
  • Journal Title: Organic Letters Volume: 21 Issue: 23 Pages: 9536-9540
  • DOI: 10.1021/acs.orglett.9b03719
  • Peer Reviewed
• [Journal Article] Photo-Induced C(sp3)-N Bond Cleavage Leading to Stereoselective Syntheses of Alkenes (2019)
  • Author(s): Ze-Kun Yang, Ning-Xin Xu, Chao Wang, and Masanobu Uchiyama
  • Journal Title: Chem. Eur. J. Volume: 25 Issue: 21 Pages: 5433-5439
  • DOI: 10.1002/chem.201900886
  • Peer Reviewed
• [Journal Article] A new route for the efficient metalation of unfunctionalized aromatics (2019)
  • Author(s): Peel Andrew J.、Tezuka Noriyuki、D'Rozario James M.、Uchiyama Masanobu、Wheatley Andrew E. H.
  • Journal Title: Chemical Science Volume: 10 Issue: 11 Pages: 3385-3400
  • DOI: 10.1039/c8sc04325f
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] In SituGeneration of Silyl Anion Species through Si-B Bond Activation for the Concerted Nucleophilic Aromatic Substitution of Fluoroarenes (2019)
  • Author(s): Kojima Kumiko、Nagashima Yuki、Wang Chao、Uchiyama Masanobu
  • Journal Title: ChemPlusChem Volume: 84 Issue: 3 Pages: 277-280
  • DOI: 10.1002/cplu.201900069
  • Peer Reviewed
• [Journal Article] Aromatic butenolides produced by a soil ascomycete Auxarthron sp. KCB15F070 derived from a volcanic island (2019)
  • Author(s): Kim Jong Won、Son Sangkeun、Kim Gil Soo、Otaka Junnosuke、Miura Yuzuki、Muranaka Atsuya、Uchiyama Masanobu、Lee Jung-Sook、Jang Mina、Ko Sung-Kyun、Takahashi Shunji、Osada Hiroyuki、Jang Jae-Hyuk、Ahn Jong Seog
  • Journal Title: Tetrahedron Letters Volume: 60 Issue: 45 Pages: 151227-151227
  • DOI: 10.1016/j.tetlet.2019.151227
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Inherent atomic mobility changes in carbocation intermediates during the sesterterpene cyclization cascade (2019)
  • Author(s): Sato Hajime、Mitsuhashi Takaaki、Yamazaki Mami、Abe Ikuro、Uchiyama Masanobu
  • Journal Title: Beilstein Journal of Organic Chemistry Volume: 15 Pages: 1890-1897
  • DOI: 10.3762/bjoc.15.184
  • Peer Reviewed / Open Access
• [Remarks] 東京大学大学院薬学系研究科 基礎有機化学教室
  • URL: http://www.f.u-tokyo.ac.jp/~kisoyuki/publication.html