Continuous flow synthesis by integrated reactions: Efficient synthesis and transformation of naturally occurring bioactive middle molecules

• Project Area: Middle molecular strategy: Creation of higher bio-functional molecules by integrated synthesis.
• Project/Area Number: 18H04411
• Research Category: Grant-in-Aid for Scientific Research on Innovative Areas (Research in a proposed research area)
• Allocation Type: Single-year Grants
• Research Institution: Osaka University
• Principal Investigator: 赤井 周司 大阪大学, 薬学研究科, 教授 (60192457)
• Project Period (FY): 2018-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000); Fiscal Year 2019: ¥2,600,000 (Direct Cost: ¥2,000,000、Indirect Cost: ¥600,000); Fiscal Year 2018: ¥2,600,000 (Direct Cost: ¥2,000,000、Indirect Cost: ¥600,000)
• Keywords: 加水分解酵素 / 触媒 / フロー合成 / 生物機能分子 / 動的速度論的光学分割 / 不斉合成 / フッ素化 / 集積型反応 / 連続フロー合成 / 酵素触媒反応 / 動的光学分割 / 生物機能中分子

Outline of Annual Research Achievements

複数の触媒を同時に用いて、複数の反応をワンポットで進行させることができれば、反応工程の短縮（集積化）、操作や廃棄物の軽減だけでなく、単独の触媒では成しえなかった高次の変換が可能になる。申請者は最近、その成功例として、加水分解酵素リパーゼと固定化バナジウムV-MPSを同時に用いる動的速度論的光学分割法を開発した。また、申請者はカテコール類のデオキシフルオロ化によるフッ素置換芳香族化合物の合成法を開発した。本研究では、これらの集積型変換法をフロー合成などに発展させて、生物機能分子の短工程不斉合成や、構造修飾法を開発することを目的とする。本年度、当初の計画に従って研究を行い、以下の成果を得た。
１．固定化リパーゼとラセミ化触媒を混合充填したカラムリアクターを用いて、ラセミの第２級アルコールの連続フロー型の動的速度論的光学分割に成功した。本法は３日間連続稼働できることも分かった。
２．ポリヒドロキシ軸不斉ビアリール化合物のリパーゼ触媒非対称化法を開発した。本法は、一つの基質から、両方の鏡像異性体を高収率・高光学純度で作り分ける有用な方法論を提供できる。
３．我々が開発した軸不斉ビアリール化合物の動的速度論的光学分割法を、複素環を含むビアリール類に適用拡張すべく、他の班員との共同研究を実施中である。
４．カテコール類のデオキシフルオロ化法をピロガロール環を含む化合物群に適用した。その際、一つの水酸基に適切な保護基導入することで、残る２つの水酸基のフッ素化の位置を２通りに制御できることを見出した。現在、本法を生物活性ポリヒドロキシビフェニル化合物に適用して、含フッ素生物機能分子の創出を目指している。

Research Progress Status

令和元年度が最終年度であるため、記入しない。

Strategy for Future Research Activity

令和元年度が最終年度であるため、記入しない。

Research Products

• [Int'l Joint Research] ビーレフェルト大学(ドイツ)
• [Journal Article] Continuous-Flow Dynamic Kinetic Resolution of Racemic Alcohols by Lipase-Oxovanadium Cocatalysis (2020)
  • Author(s): 1.Koichi Higashio, Satoko Katsuragi, Dhiman Kundu, Niklas Adebar, Carmen Plass, Franziska Kuehn, Harald Groeger, Shuji Akai
  • Journal Title: Eur. J. Org. Chem. Volume: - Issue: 13 Pages: 1961-1967
  • DOI: 10.1002/ejoc.202000186
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Dynamic kinetic resolution of a tertiary alcohol (2020)
  • Author(s): 2.Franziska Kuehn, Satoko Katsuragi, Yasuhiro Oki, Cedric Scholz, Shuji Akai, Harald Groeger
  • Journal Title: Chem. Commun. Volume: 56 Issue: 19 Pages: 2885-2888
  • DOI: 10.1039/c9cc09103c
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Enantiodivergent Synthesis of Axially Chiral Biphenyls from σ-Symmetric 1,1'-Biphenyl-2,6-diol Derivatives by Single Lipase-Catalyzed Acylative and Hydrolytic Desymmetrization (2020)
  • Author(s): Kasama Kengo、Aoyama Hiroshi、Akai Shuji
  • Journal Title: European Journal of Organic Chemistry Volume: 2020 Issue: 6 Pages: 654-661
  • DOI: 10.1002/ejoc.201901583
  • Peer Reviewed
• [Journal Article] 4.Lipase/Oxovanadium Co-Catalyzed Dynamic Kinetic Resolution of Propargyl Alcohols: Competition between Racemization and Rearrangement (2019)
  • Author(s): Shinji Kawanishi, Shinya Oki, Dhiman Kundu, Shuji Akai
  • Journal Title: Org. Lett. Volume: 21 Issue: 9 Pages: 2978-2982
  • DOI: 10.1021/acs.orglett.9b00334
  • Peer Reviewed
• [Journal Article] 3.Base-promoted Lipase-catalyzed Kinetic Resolution of Atropisomeric 1,1’-Biaryl-2,2’-diols (2019)
  • Author(s): Gamal A. I. Moustafa, Kengo Kasama, Koichi Higashio, Shuji Akai
  • Journal Title: RSC Adv. Volume: 9 Issue: 3 Pages: 1165-1175
  • DOI: 10.1039/c8ra09070j
  • Peer Reviewed / Open Access
• [Journal Article] Ammonium Salt-Accelerated Hydrazinolysis of Unactivated Amides: Mechanistic Investigation and Application to a Microwave Flow Process (2019)
  • Author(s): Noshita, M.; Shimizu, Y.; Morimoto, H.; Akai, S.; Hamashima, Y.; Ohneda, N.; Odajima, H.; Ohshima, T.
  • Journal Title: Org. Process Res. Dev. Volume: - Issue: 4 Pages: 588-594
  • DOI: 10.1021/acs.oprd.8b00424
  • Peer Reviewed
• [Journal Article] Microflow Fluorinations of Benzynes: Efficient Synthesis of Fluoroaromatic Compounds (2018)
  • Author(s): Ikawa Takashi、Masuda Shigeaki、Akai Shuji
  • Journal Title: Chemical and Pharmaceutical Bulletin Volume: 66 Issue: 12 Pages: 1153-1164
  • DOI: 10.1248/cpb.c18-00578
  • NAID: 130007539120
  • ISSN: 0009-2363, 1347-5223
  • Year and Date: 2018-12-01
  • Peer Reviewed / Open Access
• [Journal Article] Flow Synthesis of (3R)- and (3S)-(E)-1-Iodohexa-1,5-dien-3-ol: Chiral Building Blocks for Natural Product Synthesis (2018)
  • Author(s): Katayama Sota、Koge Tomoyuki、Katsuragi Satoko、Akai Shuji、Oishi Tohru
  • Journal Title: Chemistry Letters Volume: 47 Issue: 9 Pages: 1116-1118
  • DOI: 10.1246/cl.180475
  • NAID: 130007472093
  • Peer Reviewed / Open Access
• [Journal Article] Lipase-catalyzed asymmetric synthesis of naphtho[2,3-c]furan-1(3H)-one derivatives by a one-pot dynamic kinetic resolution/intramolecular Diels-Alder reaction: Total synthesis of (－)-himbacine (2018)
  • Author(s): Koji Sugiyama, Shinji Kawanishi, Yasuhiro Oki, Marin Kamiya, Ryosuke Hanada, Masahiro Egi, Shuji Akai
  • Journal Title: Bioorganic & Medicinal Chemistry Volume: 26 Issue: 7 Pages: 1378-1386
  • DOI: 10.1016/j.bmc.2017.08.019
  • Peer Reviewed
• [Presentation] 非対称な軸不斉ビアリール化合物のリパーゼ触媒動的速度論的光学分割法の開発 (2020)
  • Author(s): 笠間建吾、日南優也、Moustafa Gamal A. I、朴韓晳、佐古真、東田恵伍、滝澤忍、笹井宏明、赤井周司
  • Organizer: 日本薬学会第140年会
• [Presentation] 加水分解酵素リパーゼだからできる新しい不斉合成術 (2020)
  • Author(s): 赤井周司
  • Organizer: 有機合成2月セミナー「有機合成のニュートレンド2020」
  • Invited
• [Presentation] 単一リパーゼによる軸不斉ビアリール化合物の両鏡像異性体の作り分け (2020)
  • Author(s): 赤井周司
  • Organizer: 新学術領域研究「反応集積化が導く中分子戦略:高次生物機能分子の創製」令和１年度第９回成果報告会
• [Presentation] Lipase/Transition Metal Cocatalyzed Dynamic Kinetic Resolution of Racemic Alcohols: From Batch to Flow (2019)
  • Author(s): Shuji Akai
  • Organizer: 13th International CeBiTec Symposium
  • Int'l Joint Research / Invited
• [Presentation] Synergy of Enzymes and Transition Metals: Quantitative Conversion of Racemates into Optically Pure Forms (2019)
  • Author(s): Shuji Akai
  • Organizer: Special lecture at University of Goettingen
  • Int'l Joint Research / Invited
• [Presentation] Lipase-Catalyzed Continuous Flow Dynamic Kinetic Resolution of Racemic Alcohols (2019)
  • Author(s): Koichi Higashio, Satoko Katsuragi, Franziska Kuehn, Niklas Adebar, Carmen Plass, Harald Groeger, Shuji Akai
  • Organizer: International Joint Symposium on Synthetic Organic Chemistry
  • Int'l Joint Research
• [Presentation] ビリジンの合成研究―集積した官能基の位置及び立体選択的構築― (2019)
  • Author(s): 堀修平、杉山公二、八幡健三、赤井周司
  • Organizer: 第69回日本薬学会関西支部総会・大会
• [Presentation] Chemoenzymatic Access to Axially Chiral Biaryl-2,2′-diols (2019)
  • Author(s): Shuji Akai
  • Organizer: The 8th Japanese-Sino Symposium on Organic Chemistry for Young Scientists
  • Int'l Joint Research / Invited
• [Presentation] Hydrolase Transition Metal Co-catalyzed Dynamic Kinetic Resolution: Quantitative Conversion of Racemates into Optically Pure Molecules (2019)
  • Author(s): Shuji Akai
  • Organizer: The 2nd JGP Chem & ChemEn International Workshop: Sustainability-Oriented Organic Synthesis
  • Int'l Joint Research / Invited
• [Presentation] Synthetic study of the furanosteroid, viridin (2019)
  • Author(s): Shuhei Hori, Koji Sugiyama, Kenzo Yahata and Shuji Akai
  • Organizer: 27th International Society of Heterocyclic Chemistry Congress
  • Int'l Joint Research
• [Presentation] Enantiodivergent and Quantitative Conversion of Racemic Propargyl Alcohols into Their Both Enantiomers Using Lipase-Catalyzed Dynamic Kinetic Resolution (2019)
  • Author(s): Shinji Kawanishi, Koichi Higashio, Shinya Oki, Shuji Akai
  • Organizer: 27th International Society of Heterocyclic Chemistry Congress
  • Int'l Joint Research
• [Presentation] A Biocatalytic Highly Enantioselective Synthesis of Axially Chiral Bihydroxycarbazoles (2019)
  • Author(s): Kengo Kasama, Gamal A. I. Moustafa, Hanseok Park, Makoto Sako, Keigo Higashida, Shinobu Takizawa, Hiroaki Sasai, and Shuji Akai
  • Organizer: 27th International Society of Heterocyclic Chemistry Congress
  • Int'l Joint Research
• [Presentation] リパーゼ触媒を用いたアルコールの連続フロー動的光学分割法の開発 (2019)
  • Author(s): 東尾 光一, 桂木 智子, Franziska Kuehn, Niklas Adebar, Carmen Plass,Harald Groeger , 赤井 周司
  • Organizer: 第21回生体触媒化学シンポジウム
• [Presentation] 同一リパーゼによる軸不斉ビアリール化合物の両光学異性体の作り分け (2019)
  • Author(s): 笠間建吾、青山 浩、赤井周司
  • Organizer: 第21回生体触媒化学シンポジウム
• [Presentation] viridinの合成研究 (2019)
  • Author(s): 堀修平、杉山公二、八幡健三、赤井周司
  • Organizer: 第39回有機合成若手セミナー
• [Presentation] Continuous Flow Lipase-Catalyzed Dynamic Kinetic Resolution of Alcohols (2019)
  • Author(s): Koichi Higashio, Satoko Katsuragi, Franziska Kuehn, Niklas Adebar, Carmen Plass, Harald Groeger, Shuji Akai
  • Organizer: 第4回プロセス化学国際シンポジウム
  • Int'l Joint Research
• [Presentation] Lipase-catalyzed Desymmetrization of σ-Symmetric Biaryl Diols for the Enantiodivergent Synthesis of Axially Chiral Biaryls (2019)
  • Author(s): Kengo Kasama, Shuji Akai
  • Organizer: The 11th Seoul-Kyoto-Osaka Joint Symposium On Pharmaceutical Sciences For Young Scientists
  • Int'l Joint Research
• [Presentation] リパーゼ触媒動的光学分割法によるプロパルギルアルコールの両エナンチオマーの作り分け (2019)
  • Author(s): 赤井周司
  • Organizer: 新学術領域研究「反応集積化が導く中分子戦略:高次生物機能分子の創製」令和１年度第８回成果報告会
• [Presentation] Enantiodivergent Atroposelective Synthesis of Chiral Biaryl Diols by Lipase-catalyzed Desymmetrization (2019)
  • Author(s): Kengo Kasama, Shuji Akai
  • Organizer: The 27th French-Jpanese Symposium on Medicinal and Fine Chemistry
  • Int'l Joint Research
• [Presentation] Lipase-metal Combo Catalyzed Dynamic Kinetic Resolution (2019)
  • Author(s): Shuji Akai
  • Organizer: サンクトペテルブルグ州立大学特別講義
  • Int'l Joint Research / Invited
• [Presentation] ピロガロール類の位置選択的脱酸素フッ素化法の開発 (2019)
  • Author(s): 東 雅之、里 章平、田窪景太、春田純一、赤井周司
  • Organizer: 日本薬学会第139回年会
• [Presentation] 加水分解酵素と遷移金属の触媒集積化：新しい不斉合成法への挑戦 (2018)
  • Author(s): 赤井周司
  • Organizer: 昭和薬科大学特別講義
  • Invited
• [Presentation] Lipase/Metal Combo-Catalysis for Dynamic Kinetic Resolution: Quantitative Conversion of Racemates into Optically Pure Molecules (2018)
  • Author(s): Shuji Akai
  • Organizer: 8th Catalysis & Fine Chemicals 2018
  • Int'l Joint Research / Invited
• [Presentation] Continuous Microflow Reactions for Deoxyfluorination of Substituted Phenols into Fluorobenzenes (2018)
  • Author(s): Takashi Ikawa, Shigeaki Masuda and Shuji Akai
  • Organizer: The 4th International Symposium on Middle Molecular Strategy (ISMMS-4)
  • Int'l Joint Research
• [Presentation] A Modular Biocatalytic Approach for the Highly Enantioselective Synthesis of Atropisomeric Biaryl Diols (2018)
  • Author(s): Kengo Kasama, Koichi Higashio, Gamal A. I. Moustafa, Shuji Akai
  • Organizer: The 14th International Kyoto Conference on New Aspects of Organic Chemistry
  • Int'l Joint Research
• [Presentation] Lipase/Metal Combo-Catalyzed Dynamic Kinetic Resolution: Quantitative Conversion of Racemates into Optically Pure Molecules (2018)
  • Author(s): 赤井周司
  • Organizer: International Congress on Pure & Applied Chemistry Langkawi (ICPAC Langkawi 2018)
  • Int'l Joint Research / Invited
• [Presentation] 加水分解酵素リパーゼが拓く新しい不斉合成 (2018)
  • Author(s): 赤井周司
  • Organizer: 金沢大学薬学シンポジウム
  • Invited
• [Presentation] O-Protecting Group Effect on Regioselectivity of Dienone-Phenol Rearrangement of 4,4-Disubstituted 2-Hydroxycyclohexa-2,5-dienones and Related Difluorides. (2018)
  • Author(s): Ahmed AbuBakr, Shuji Akai
  • Organizer: 第68回日本薬学会近畿支部総会・大会
• [Presentation] Synergy of lipases with metal catalysts for dynamic kinetic resolution of racemic alcohols and binaphthols (2018)
  • Author(s): Shuji Akai
  • Organizer: Bielefeld大学特別講演
  • Invited
• [Presentation] Regioselectivity of Dienone-Phenol Rearrangement of 4,4-Disubstituted 2-Hydroxycyclohexa-2,5-dienone Derivatives and Corresponding Difluorides (2018)
  • Author(s): Ahmed AbuBakr,Shuji Akai
  • Organizer: International Symposium on Main Group Chemistry Directed towards Organic Synthesis (MACOS)
  • Int'l Joint Research
• [Presentation] 異種触媒集積型分子変換の最先端 (2018)
  • Author(s): 赤井周司
  • Organizer: 第26回分子合成化学セミナー
• [Presentation] 酵素と金属の触媒集積型動的光学分割の新展開 (2018)
  • Author(s): 赤井周司
  • Organizer: 新学術領域研究「反応集積化が導く中分子戦略:高次生物機能分子の創製」平成30年度第6回成果報告会
• [Book] Kinetic Control in Synthesis and Self-Assembly (2018)
  • Author(s): Shuji Akai and Gamal A. I. Moustafa
  • Total Pages: 324
  • Publisher: Academic Press
  • ISBN: 9780128121269
• [Remarks] 大阪大学大学院 薬学研究科 薬品製造化学分野 ホームページ
  • URL: https://handai-seizo.jp/
• [Remarks] 大阪大学大学院薬学研究科 薬品製造化学分野 ホームページ
  • URL: http://handai-seizo.jp/
• [Patent(Industrial Property Rights)] 充填層及びそれを用いた流通方法 (2019)
  • Inventor(s): 宮本利一、白 鴻志、赤井周司、東尾光一
  • Industrial Property Rights Holder: 宮本利一、白 鴻志、赤井周司、東尾光一
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2019-239305
  • Filing Date: 2019