Reaction Development Empowered by Peculiar B3NO2 Heterocycle

• Project Area: Precise Formation of a Catalyst Having a Specified Field for Use in Extremely Difficult Substrate Conversion Reactions
• Project/Area Number: 18H04276
• Research Category: Grant-in-Aid for Scientific Research on Innovative Areas (Research in a proposed research area)
• Allocation Type: Single-year Grants
• Research Institution: Microbial Chemistry Research Foundation
• Principal Investigator: 熊谷 直哉 公益財団法人微生物化学研究会, 微生物化学研究所, 主席研究員 (40431887)
• Project Period (FY): 2018-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥6,240,000 (Direct Cost: ¥4,800,000、Indirect Cost: ¥1,440,000); Fiscal Year 2019: ¥3,120,000 (Direct Cost: ¥2,400,000、Indirect Cost: ¥720,000); Fiscal Year 2018: ¥3,120,000 (Direct Cost: ¥2,400,000、Indirect Cost: ¥720,000)
• Keywords: ヘテロ環 / 新規骨格 / 触媒反応 / 反応開発 / 協奏機能 / アミド化 / 触媒 / 原子効率 / ホウ素

Outline of Annual Research Achievements

DATB はその簡略化型分子よりも有意に高い触媒活性を示すことがわかっており，DATBが有する下部ヒドロキシアザボリンユニットが反応に関与することが示唆されていた。カルボン酸とDATBとの相互作用が分光学的手法で補足できないため，DFT計算による遷移状態探索を行った。アミンは下部ホウ素へ配位することが実験的に明示されており，配位安定化が計算でも再現された。一方，2つの上部ホウ素部位は中央窒素がカルボン酸からプロトン化を受けることで十分なLewis酸性を獲得し，カルボン酸の活性化を起こすことが示され，その遷移状態においてDATBはアザボリンユニットがカルボン酸と水素結合することで，簡略化型分子よりも有利に反応が進行することを見出した。また，アミンの付加段階においてもアザボリンユニットと主骨格のm-ターフェニルユニット間にπコンタクトがみられ，2種の非共有結合性相互作用による遷移状態安定化によりDATBが簡略化型分子を凌駕する高い触媒活性を発現していると考えられる。続いて安価に合成可能なDATB類縁体の導出を試みた。対称構造の一挙構築と簡便なホウ素導入を目論み，安価なピリミジン化合物を出発原料とする誘導体Pym-DATBを得るカラムフリーの3工程合成法を確立した。このPym-DATBは低コストで量産可能で，m-terphenyl型のDATB と同等の触媒活性並びに基質一般性を発現することを明らかにした。新合成法は周辺骨格への各種置換基導入も可能にし，置換基の立体電子効果に関する知見に加え，各種有機溶媒に易溶な類縁体の導出にも至り，固相合成への適用も期待される。抜粋した適用例に示すように，立体障害性置換基，極性・酸感受性官能基は幅広く許容される。

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

• [Journal Article] Z-Enolate Geometry in the Thioamide Aldol Reaction Illuminated by the 7-Azaindoline Auxiliary (2020)
  • Author(s): Roman Pluta, Zhao Li, Naoya Kumagai*, and Masakatsu Shibasaki*
  • Journal Title: Org. Lett. Volume: 22 Issue: 3 Pages: 791-794
  • DOI: 10.1021/acs.orglett.9b04120
  • Peer Reviewed
• [Journal Article] (2R,3S)‐3,4,4,4‐Tetrafluorovaline: A Fluorinated Bioisostere of Isoleucine (2020)
  • Author(s): Lennart Brewitz, Hidetoshi Noda, Naoya Kumagai*, Masakatsu Shibasaki*
  • Journal Title: Eur. J. Org. Chem. Volume: 2020 Issue: 11 Pages: 1745-1752
  • DOI: 10.1002/ejoc.202000109
  • Peer Reviewed / Open Access
• [Journal Article] Introduction of a 7-aza-6-MeO-indoline auxiliary in Lewis-acid/photoredox cooperative catalysis: highly enantioselective aminomethylation of α,β-unsaturated amides (2020)
  • Author(s): Santosh K. Pagire, Naoya Kumagai* and Masakatsu Shibasaki*
  • Journal Title: Chem. Sci. Volume: 2020 Issue: 20 Pages: 5168-5174
  • DOI: 10.1039/d0sc01890b
  • Peer Reviewed / Open Access
• [Journal Article] A Thirst for Enantioselectivity in Catalytic Addition of Alkylnitriles (2019)
  • Author(s): Naoya Kumagai* and Masakatsu Shibasaki*
  • Journal Title: Chem. Lett. Volume: 48 Issue: 11 Pages: 1322-1327
  • DOI: 10.1246/cl.190609
  • NAID: 130007741817
  • Peer Reviewed / Open Access
• [Journal Article] Direct Catalytic Asymmetric Addition of Acetonitrile to Aldimines (2019)
  • Author(s): Akira Saito, Naoya Kumagai*, and Masakatsu Shibasaki*
  • Journal Title: Org. Lett. Volume: 21 Issue: 20 Pages: 8187-8190
  • DOI: 10.1021/acs.orglett.9b02821
  • Peer Reviewed
• [Journal Article] Direct Catalytic Asymmetric Mannich-Type Reaction of an α-CF3 Amide to Isatin Imines (2019)
  • Author(s): Yu, J.-S.; Noda, H.; Kumagai, N.; Shibasaki, M.
  • Journal Title: Synlett Volume: 30 Issue: 04 Pages: 488-492
  • DOI: 10.1055/s-0037-1611642
  • Peer Reviewed / Open Access
• [Journal Article] Achiral Trisubstituted Thioureas as Secondary Ligands to Cu(I) Catalysts: Direct Catalytic Asymmetric Addition of α-Fluoronitriles to Imines (2019)
  • Author(s): Pandur Venkatesan Balaji, Lennart Brewitz, Naoya Kumagai,* and Masakatsu Shibasaki*
  • Journal Title: Angew. Chem. Int. Ed. Volume: 58 Issue: 9 Pages: 2644-2648
  • DOI: 10.1002/anie.201812673
  • Peer Reviewed
• [Journal Article] 7-Azaindoline Auxiliary: A Versatile Attachment Facilitating Enantioselective C-C Bond-Forming Catalysis (2019)
  • Author(s): Naoya Kumagai,* and Masakatsu Shibasaki*
  • Journal Title: Synthesis Volume: 51 Issue: 01 Pages: 185-193
  • DOI: 10.1055/s-0037-1610412
  • Peer Reviewed
• [Journal Article] Catalytic Asymmetric Synthesis of syn-Aldols with Methyl Ketone Functionality and anti-Aldol with a Thioamide (2019)
  • Author(s): Yuya Ota, Zhao Li, Naoya Kumagai,* and Masakatsu Shibasaki*
  • Journal Title: Synlett Volume: 30 Issue: 05 Pages: 620-624
  • DOI: 10.1055/s-0037-1610690
  • Peer Reviewed
• [Journal Article] A fluorogenic C4N4 probe for azide-based labelling (2019)
  • Author(s): Noda, H.; Asada, Y.; Shibasaki, M.; Kumagai, N.
  • Journal Title: Org. Biomol. Chem. Volume: 17 Issue: 7 Pages: 1813-1816
  • DOI: 10.1039/c8ob02695e
  • Peer Reviewed
• [Journal Article] Neighboring Protonation Unveils Lewis Acidity in the B3NO2 Heterocycle (2019)
  • Author(s): Noda, H.; Asada, Y.; Shibasaki, M.; Kumagai, N.
  • Journal Title: J. Am. Chem. Soc. Volume: 141 Issue: 4 Pages: 1546-1554
  • DOI: 10.1021/jacs.8b10336
  • Peer Reviewed
• [Journal Article] Direct Catalytic Asymmetric Aldol Reaction of α-Alkoxyamides to α-Fluorinated Ketones (2019)
  • Author(s): Roman Pluta, Naoya Kumagai,* and Masakatsu Shibasaki*
  • Journal Title: Angew. Chem. Int. Ed. Volume: 58 Issue: 8 Pages: 2459-2463
  • DOI: 10.1002/anie.201814607
  • Peer Reviewed
• [Journal Article] A C4N4 Diaminopyrimidine Fluorophore (2019)
  • Author(s): Noda, H.; Asada, Y.; Maruyama, T.; Takizawa, N.; Noda, N. N.; Shibasaki, M.; Kumagai, N.
  • Journal Title: Chem. Eur. J. Volume: 25 Issue: 17 Pages: 4299-4304
  • DOI: 10.1002/chem.201900467
  • Peer Reviewed
• [Journal Article] All Non-Carbon B3NO2 Exotic Heterocycle: Synthesis, Dynamics, and Catalysis (2019)
  • Author(s): Opie, C. R.; Noda, H.; Shibasaki, M.; Kumagai, N.
  • Journal Title: Chem. Eur. J. Volume: 25 Issue: 18 Pages: 4648-4653
  • DOI: 10.1002/chem.201900715
  • Peer Reviewed
• [Journal Article] Solvent-Dependent Enantio-divergence in anti-Selective Catalytic Asymmetric Nitroaldol Reactions (2019)
  • Author(s): Tomoya Karasawa, Akira Saito, Naoya Kumagai*, Masakatsu Shibasaki*
  • Journal Title: Org. Lett. Volume: 21 Issue: 10 Pages: 3581-3583
  • DOI: 10.1021/acs.orglett.9b00982
  • Peer Reviewed
• [Journal Article] anti-Selective Catalytic Asymmetric Nitroaldol Reaction of α-Keto Esters: Intriguing Solvent Effect, Flow Reaction, and Synthesis of Active Pharmaceutical Ingredients (2018)
  • Author(s): Tomoya Karasawa, Raphael Oriez, Naoya Kumagai,* and Masakatsu Shibasaki*
  • Journal Title: J. Am. Chem. Soc. Volume: 140 Issue: 38 Pages: 12290-12295
  • DOI: 10.1021/jacs.8b08236
  • Peer Reviewed
• [Presentation] アセトニトリルを基質とするダイレクト型触媒的不斉付加反応 (2020)
  • Author(s): 齊藤 誠、熊谷 直哉、柴崎 正勝
  • Organizer: 日本薬学会第140年会
• [Presentation] Featuring unique 7-azaindoline auxiliaries in the cooperative Lewis-acid and visible-light photocatalysis: enantioselective synthesis of γ-aminobutyramides (2020)
  • Author(s): PAGIRE Santosh Kisan、熊谷 直哉、柴崎 正勝
  • Organizer: 日本薬学会第140年会
• [Presentation] Achiral Thioureas as Ancillary Ligands to Cu(I) Catalysts: Remarkable Enhancement of Stereocontrol in Direct Catalytic Asymmetric Addition of alpha-Fluoronitriles to Aldehydes (2020)
  • Author(s): パンドル バラジ、熊谷 直哉、柴崎 正勝
  • Organizer: 日本薬学会第140年会
• [Presentation] 7-Azaindoline Thioamide: Unveiling the Geometry of Enolate in Direct Aldol Reaction (2020)
  • Author(s): ロマン プルタ、李 釗、熊谷 直哉、柴﨑 正勝
  • Organizer: 日本薬学会第140年会
• [Presentation] Direct Catalytic Asymmteic Aldol Reaction of α-Alkoxyamides to α-Fluorineated Ketones. (2019)
  • Author(s): Roman Pluta, 熊谷直哉, 柴崎正勝
  • Organizer: 第17回次世代を担う有機化学シンポジウム
• [Presentation] Chemistry Empowered by Unique Heterocycles. (2019)
  • Author(s): Naoya Kumagai
  • Organizer: 第29回光学活性シンポジウム
  • Int'l Joint Research / Invited
• [Presentation] Chemistry Empowered by Unique Heterocycles (2019)
  • Author(s): Naoya Kumagai
  • Organizer: University College London
  • Invited
• [Presentation] Systematic Examination of Catalytic Amide Bond Formation by the Readily Accessible B3NO2 Heterocycle-Containing Molecule Pym-DATB (2019)
  • Author(s): Christopher R. Opie, Hidetoshi Noda, Masakatsu Shibasaki, Naoya Kumagai
  • Organizer: 27th International Society of Heterocyclic Chemistry Congress
  • Int'l Joint Research
• [Presentation] Enantioselective Photocatalysis with Unique 7-Azaindoline Auxiliaries Opportunities and Challenges (2019)
  • Author(s): Santosh K. Pagire, Naoya Kumagai, Masakatsu Shibasaki
  • Organizer: 27th International Society of Heterocyclic Chemistry Congress
  • Int'l Joint Research
• [Presentation] 特殊ヘテロ環の化学 (2019)
  • Author(s): 熊谷直哉
  • Organizer: 静岡県立大学
  • Invited
• [Presentation] Chemistry Empowered by Unique Heterocycles (2019)
  • Author(s): Naoya Kumagai
  • Organizer: Otsu Conference
  • Invited
• [Presentation] アセトニトリルのダイレクト型触媒的不斉付加反応 (2019)
  • Author(s): 齊藤誠，熊谷直哉，柴崎正勝
  • Organizer: 第45回反応と合成の進歩シンポジウム
• [Presentation] Featuring New 7-Azaindolines Auxiliaries for the Enantioselective Photocatalytic Synthesis of GABA Derivatives (2019)
  • Author(s): Santosh K. Pagire，熊谷直哉，柴崎正勝
  • Organizer: 第45回反応と合成の進歩シンポジウム
• [Presentation] 特殊ヘテロ環を駆使する触媒反応 (2019)
  • Author(s): 熊谷直哉
  • Organizer: 第14回プロセス化学ラウンジ 富士フィルム和光純薬湯河原研修所
  • Invited
• [Presentation] Catalytic Function Dictated by the B3NO2 Ring System (2019)
  • Author(s): Naoya Kumagai
  • Organizer: 4th International Symposium on Precisely Designed Catalysts with Customized Scaffolding Kinsho Hall in Todaiji Culture Center
  • Int'l Joint Research / Invited
• [Presentation] 特殊ヘテロ環の化学 (2019)
  • Author(s): 熊谷直哉
  • Organizer: 高砂香料株式会社 平塚研究所
  • Invited
• [Presentation] 特殊ヘテロ環による触媒反応 (2019)
  • Author(s): 熊谷直哉
  • Organizer: 新学術領域研究「高難度物質変換反応の開発を指向した精密制御反応場の創出」第６回公開シンポジウム
  • Invited
• [Presentation] Chemistry Empowered by Unique Heterocycles (2019)
  • Author(s): Naoya Kumagai
  • Organizer: 日本化学会第99年会
  • Invited
• [Presentation] Direct Catalytic Asymmetric Aldol Reaction of α-Vinyl Thioamide and Amide and their Applications in Enantioselective Synthesis of Natural Products (2019)
  • Author(s): Jin CUI, 竹内 倫文, 大朏 彰道, 渡辺 匠, 熊谷 直哉, 柴崎 正勝
  • Organizer: 日本薬学会第139年会
• [Presentation] α-ケトエステルのanti選択的触媒的不斉ニトロアルドール反応 (2019)
  • Author(s): 柄澤 智哉, Raphael ORIEZ, 熊谷 直哉, 柴﨑 正勝
  • Organizer: 日本薬学会第139年会
• [Presentation] Lewis酸/光触媒系によるGABA誘導体の不斉合成法の開発 (2019)
  • Author(s): Santosh Kisan PAGIRE, 熊谷 直哉, 柴﨑 正勝
  • Organizer: 日本薬学会第139年会
• [Presentation] B3NO2型ヘテロ環化合物Pym-DATBによる触媒的アミド化反応 (2019)
  • Author(s): Christopher Roderick OPIE, 野田 秀俊, 柴崎 正勝, 熊谷 直哉
  • Organizer: 日本薬学会第139年会
• [Presentation] 新規C4N4フルオロフォア (2019)
  • Author(s): 野田 秀俊, 朝田 康子, 丸山 達朗, 滝沢 直己, 野田 展生, 柴﨑 正勝, 熊谷 直哉
  • Organizer: 日本薬学会第139年会
• [Presentation] Direct Catalytic Asymmetric Aldol Reaction of Amides in the Synthesis of Fluorinated α, β-Dihydroxy Acids (2019)
  • Author(s): Roman PLUTA, 熊谷 直哉, 柴崎 正勝
  • Organizer: 日本薬学会第139年会
• [Presentation] Achiral Trisubstituted Thioureas as Secondary Ligands to Cu(I) Catalysts: Direct Catalytic Asymmetric Addition of alpha-Fluoronitriles to Imines (2019)
  • Author(s): Pandur BALAJI, Lennart BREWITZ, 熊谷 直哉, 柴崎 正勝
  • Organizer: 日本薬学会第139年会
• [Presentation] Direct catalytic asymmetric Mannich-type reaction of an α -CF3 amide to isatin imines supported by mechanistic study on bis(tetrahydrophosphole)-type ligands (2019)
  • Author(s): 余 金生, 李 釗, 野田 秀俊, 熊谷 直哉, 柴﨑 正勝
  • Organizer: 日本薬学会第139年会
• [Presentation] 複核ホウ素ヘテロ環を触媒とする直接的アミド化反応の反応機構解析 (2018)
  • Author(s): 野田秀俊、朝田康子、柴崎正勝、熊谷直哉
  • Organizer: 第16回次世代を担う有機化学シンポジウム
• [Presentation] Catalytic Function Dictated by the B3NO2 Ring System (2018)
  • Author(s): Naoya Kumagai
  • Organizer: The 1st Sino-Japanese Symposium on Catalysis for Precision Synthesis & Catalysis
  • Int'l Joint Research / Invited
• [Presentation] アミドをPlayGroundとした反応設計 (2018)
  • Author(s): 熊谷直哉
  • Organizer: 第29回万有仙台シンポジウム
  • Invited
• [Presentation] On the Mechanism of Direct Amidation Catalyzed by the B3NO2 Heterocyclic (2018)
  • Author(s): Hidetoshi Noda, Yasuko Asada, Masakatsu Shibasaki, Naoya Kumagai
  • Organizer: 24th IUPAC International Conference on Physical Organic Chemistry
  • Int'l Joint Research
• [Presentation] 特異ヘテロ環化合物の化学 (2018)
  • Author(s): 熊谷直哉
  • Organizer: 御茶の水女子大学講演
  • Invited
• [Presentation] Catalytic Function Dictated by the B3NO2 Heterocycle (2018)
  • Author(s): Naoya Kumagai
  • Organizer: CSJ-RSC Joint Symposium
  • Int'l Joint Research / Invited
• [Presentation] Chemistry Empowered by Unique Heterocycles (2018)
  • Author(s): Naoya Kumagai
  • Organizer: University of Edinburgh
  • Int'l Joint Research / Invited
• [Presentation] Chemistry Empowered by Unique Heterocycles (2018)
  • Author(s): Naoya Kumagai
  • Organizer: University of Nottingham
  • Int'l Joint Research / Invited
• [Presentation] Chemistry Empowered by Unique Heterocycles (2018)
  • Author(s): Naoya Kumagai
  • Organizer: Ludwig-Maximillians University
  • Int'l Joint Research / Invited
• [Presentation] Chemistry Empowered by Unique Heterocycles (2018)
  • Author(s): Naoya Kumagai
  • Organizer: Max-Planck Institute
  • Int'l Joint Research / Invited
• [Presentation] Chemistry Empowered by Unique Heterocycles (2018)
  • Author(s): Naoya Kumagai
  • Organizer: ETH Zurich
  • Int'l Joint Research / Invited
• [Presentation] Chemistry Empowered by Unique Heterocycles (2018)
  • Author(s): Naoya Kumagai
  • Organizer: Merck Ltd., NJ, US
  • Int'l Joint Research / Invited
• [Presentation] Chemistry Empowered by Unique Heterocycles (2018)
  • Author(s): Naoya Kumagai
  • Organizer: Sunovion Ltd., NJ, US
  • Int'l Joint Research / Invited
• [Presentation] Chemistry Empowered by Unique Heterocycles (2018)
  • Author(s): Naoya Kumagai
  • Organizer: MIT, MA, US
  • Int'l Joint Research / Invited
• [Presentation] Chemistry Empowered by Unique Heterocycles (2018)
  • Author(s): Naoya Kumagai
  • Organizer: Harvard University
  • Int'l Joint Research / Invited
• [Presentation] Chemistry Empowered by Unique Heterocycles (2018)
  • Author(s): Naoya Kumagai
  • Organizer: Caltech
  • Int'l Joint Research / Invited
• [Presentation] Chemistry Empowered by Unique Heterocycles (2018)
  • Author(s): Naoya Kumagai
  • Organizer: University of California, Berkeley
  • Int'l Joint Research / Invited
• [Presentation] Chemistry Empowered by Unique Heterocycles (2018)
  • Author(s): Naoya Kumagai
  • Organizer: Stanford University
  • Int'l Joint Research / Invited
• [Presentation] 希土類 /Na 異種 2 核金属触媒によるα - アミノ 3 級アルコールの迅速不斉合成と 医薬品合成への応用 (2018)
  • Author(s): 柄澤智哉，Raphael ORIEZ，熊谷直哉，柴﨑正勝
  • Organizer: 第44回反応と合成の進歩シンポジウム
• [Remarks] 微生物化学研究会HP
  • URL: https://www.bikaken.or.jp/research/group/shibasaki/shibasaki-lab/index.html
• [Remarks] 微生物化学研究会
  • URL: http://www.bikaken.or.jp