ワンポット集積化を基盤とする生物活性含窒素多環式天然物の合成

• Project Area: Organic Synthesis based on Integration of Chemical Reactions. New Methodologies and New Materials
• Project/Area Number: 21106006
• 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: Hokkaido University
• Principal Investigator: 橋本 俊一 北海道大学, 薬学研究科(研究院), 教授 (80107391)
• Co-Investigator(Kenkyū-buntansha): 南部 寿則 富山大学, 医学薬学研究部(薬学), 准教授 (80399956) ; 穴田 仁洋 北海道大学, 薬学研究科(研究院), 准教授 (90344473) ; 坪和 幸司 (竹田幸司) 北海道大学, 薬学研究科(研究院), 助教 (00572497)
• Project Period (FY): 2009-07-23 – 2014-03-31
• Project Status: Declined (Fiscal Year 2013)
• Budget Amount: ¥51,610,000 (Direct Cost: ¥39,700,000、Indirect Cost: ¥11,910,000); Fiscal Year 2013: ¥10,140,000 (Direct Cost: ¥7,800,000、Indirect Cost: ¥2,340,000); Fiscal Year 2012: ¥10,140,000 (Direct Cost: ¥7,800,000、Indirect Cost: ¥2,340,000); Fiscal Year 2011: ¥10,140,000 (Direct Cost: ¥7,800,000、Indirect Cost: ¥2,340,000); Fiscal Year 2010: ¥10,140,000 (Direct Cost: ¥7,800,000、Indirect Cost: ¥2,340,000); Fiscal Year 2009: ¥11,050,000 (Direct Cost: ¥8,500,000、Indirect Cost: ¥2,550,000)
• Keywords: 不斉触媒反応 / カルボニルイリド / 1,3-双極付加環化反応 / ロジウム(II)錯体 / コプシロシン類 / アレン / インドール / 生物活性多環式化合物 / α-ジアゾ-β-ケトエステル / 不溶性高分子担持錯体 / (-)-エングレリンA / フローリアクター / ワンポット集積化 / Rh(II)錯体 / 1, 3-双極付加環化反応 / ヘテロDiels-Alder反応 / 生物活性多多環式天然物 / 全合成 / カルベン / インドールアルカロイド / 複素環化合物 / 触媒反応

Outline of Annual Research Achievements

ロジウム(II)錯体を用いたカルボニルイリドの1,3-双極付加環化反応を機軸とする生物活性多環式化合物の触媒的不斉合成研究として、本年度は以下の成果を得た。
(1) Rh2(S-TCPTTL)4を用いてα-ジアゾ-β-ケトエステルとフェニルアレンとの付加環化反応を行うと、6位にエキソメチレンをもつ付加環化生成物が完璧なエキソ選択性かつ不斉収率99%で得られた。興味深いことに、本反応にRh2(OAc)4やRh2(O2CC7H15)4等のアキラルなロジウム(II)錯体、またはRh2(S-TCPTTL)4の母型錯体であるRh2(S-PTTL)4を用いると複雑な混合物を与えるのみであった。本法は、ベンゼン環上に種々の置換基をもつフェニルアレン誘導体が求双極子剤として適用可能であることが分かった。この結果はフェニルアレンを求双極子剤として用いるカルボニルイリドの不斉付加環化反応の初めての例となる。
(2) Rh2(S-TCPTTL)4を用いα-ジアゾ-β-ケトエステルとN-メチルインドールとの付加環化反応を行うと、エキソ配置の付加環化生成物が97%の不斉収率で得られた。付加環化体に対し、KH2PO4存在下亜鉛末を用いてトリクロロエチル基の除去とオキシブリッジの開裂を同時に行った後、シアノメチル基の導入およびヨウ化マグネシウムを用いたシクロプロパンの開裂、シアノ基の還元を経てC環の構築を行った。エナミノンをBirch還元によりβ-アミノケトンとした後、立体選択的Michael反応を経てコプシロシン類の持つ五環性骨格を構築することができた。

Current Status of Research Progress

2: Research has progressed on the whole more than it was originally planned.

Reason

α-ジアゾ-β-ケトエステルとN-メチルインドールとの不斉付加環化反応により得られた付加環化体からコプシロシン類の持つ五環性骨格を構築することができた。また、α-ジアゾ-β-ケトエステルをカルボニルイリド前駆体とする不斉付加環化反応における求双極子剤の適用範囲をフェニルアレン誘導体に拡張することができた。これらの成果はロジウム(II)錯体を用いたカルボニルイリドの不斉付加環化反応の潜在的有用性をさらに引き出すものと期待される。

Strategy for Future Research Activity

今後はF環構築と各種官能基変換を経てコプシロシン類の全合成達成を目指す。また、各種アレン化合物を求双極子剤とする不斉付加環化反応で得られた付加環化体から生物活性天然物への変換を検討する。

Research Products

• [Journal Article] A Stereocontrolled Construction of 2-Azido-2-deoxy-1,2-cis-α-galactosidic Linkages Utilizing 2- Azido-4,6-O-benzylidene-2-deoxygalactopyranosyl Diphenyl Phosphates: Stereoselective Synthesis of Mucin Core 5 and Core 7 Structures (2012)
  • Author(s): Kakita, K.
  • Journal Title: Tetrahedron Volume: 68 Issue: 25 Pages: 5005-5017
  • DOI: 10.1016/j.tet.2012.04.059
  • Peer Reviewed
• [Journal Article] Total Syntheses of (+)-Polygalolide A and (+)-Polygalolide B: Elucidation of the Absolute Stereochemistry and Biogenetic Implications (2012)
  • Author(s): Sugano, Y.
  • Journal Title: Chem. Eur. J. Volume: 18 Issue: 31 Pages: 9682-9690
  • DOI: 10.1002/chem.201200542
  • Peer Reviewed
• [Journal Article] Enantio- and Diastereoselective Hetero-Diels-Alder Reactions between 2-Aza-3-silyloxy-1, 3-butadienes and Aldehydes Catalyzed by Chiral Dirhodium(II) Carboxamidates (2012)
  • Author(s): Y. Watanabe, T. Washio, J. Krishnamurthi, M. Anada and S. Hashimoto
  • Journal Title: Chemical Communications Volume: 48 Issue: 55 Pages: 6969-6971
  • DOI: 10.1039/c2cc32876c
  • URL: http://dx.doi.org/
  • Peer Reviewed
• [Journal Article] A Polymer-Supported Chiral Fluorinated Dirhodium(II) Complex for Asymmetric Amination of Silyl Enol Ethers (2012)
  • Author(s): Oohara, T.
  • Journal Title: Adv. Synth. Catal. Volume: 354 Issue: 11-12 Pages: 2331-2338
  • DOI: 10.1002/adsc.201200219
  • URL: http://dx.doi.org/
  • Peer Reviewed
• [Journal Article] Catalytic Asymmetric Intermolecular C-H Insertion Reactions of 1,4-Cyclohexadiene with 2,4-Dimethyl-3-pentyl α-Alkyl-α-diazoacetates using Chiral Dirhodium(II) Carboxylates (2012)
  • Author(s): Goto, T.; Onozuka, T.; Kosaka, Y.; Anada, M.; Takeda, K.; Hashimoto, S.
  • Journal Title: Heterocycles Volume: 86 Issue: 2 Pages: 1647-1659
  • DOI: 10.3987/com-12-s(n)120
  • URL: http://dx.doi.org/
  • Peer Reviewed
• [Journal Article] Highly Enantioselective Cyclopropenation Reaction of 1-Alkynes with α-Alkyl-α-diazoesters Catalyzed by Dirhodium(II) Carboxylates (2011)
  • Author(s): Goto,T.; Takeda,K.；Shimada,N.;Nambu,H.; Anada,M;Shiro.M; Ando,.K; Hashimoto,S.
  • Journal Title: Angew. Chem. Int. Ed. Volume: 50 Issue: 30 Pages: 6803-6808
  • DOI: 10.1002/anie.201101905
  • URL: http://dx.doi.org/
  • Peer Reviewed
• [Journal Article] Catalytic Enantioselective C–H Functionalization of Indoles with α-Diazopropionates Using Chiral Dirhodium(II) Carboxylates: Asymmetric Synthesis of the (+)-α-Methyl-3-indolylacetic Acid Fragment of Acremoauxin A (2011)
  • Author(s): Goto, T.; Natori, Y.; Takeda, K.; Nambu, H.; Hashimoto, S.
  • Journal Title: Tetrahedron: Asymmetry. Volume: 22 Issue: 8 Pages: 907-915
  • DOI: 10.1016/j.tetasy.2011.05.011
  • NAID: 120003260036
  • Peer Reviewed
• [Journal Article] Enantio- and Diastereoselective Cyclopropanation with tert-Butyl α-Diazopropionate Catalyzed by Dirhodium(II) Tetrakis[N-tetrabromophthaloyl-(S)-tert-leucinate] (2011)
  • Author(s): Goto, T.; Takeda, K.; Anada, M.; Ando, K.; Hashimoto, S.
  • Journal Title: Tetrahedron Lett. Volume: 52 Issue: 32 Pages: 4200-4203
  • DOI: 10.1016/j.tetlet.2011.06.008
  • URL: http://dx.doi.org/
  • Peer Reviewed
• [Journal Article] Continuous Flow System with a Polymer-Supported Dirhodium(II) Catalyst: Application to Enantioselective Carbonyl Ylide Cycloaddition Reactions (2011)
  • Author(s): Takeda, K.; Oohara, T.; Shimada, N.; Nambu, H.; Hashimoto, S.
  • Journal Title: Chem. Eur. J. Volume: 17 Issue: 50 Pages: 13992-13998
  • DOI: 10.1002/chem.201102733
  • Peer Reviewed
• [Journal Article] Catalytic Enantioselective Intermolecular Cycloaddition of Diazodiketoester-Derived Carbonyl Ylides with Indoles Using Chiral Dirhodium(II) Carboxylates (2011)
  • Author(s): Shimada, N.; Oohara, T.; Krishnamurthi, J.; Nambu, H.; Hashimoto, S.
  • Journal Title: Org. Lett. Volume: 13 Issue: 23 Pages: 6284-6287
  • DOI: 10.1021/ol2027625
  • Peer Reviewed
• [Journal Article] Polymer-Supported Chiral Dirhodium (II) Complex : Highly Durable and Recyclable Catalyst for Asymmetric Intramolecular C-H Insertion Reactions (2010)
  • Author(s): K.Takeda, et al
  • Journal Title: Angewandte Chemie International Edition Volume: 49 Pages: 6979-6983
  • Peer Reviewed
• [Journal Article] Asymmetric Intermolecular N-H Insertion Reaction of Phenyldiazoacetates with Anilines Catalyzed by Achiral Dirhodium (II) Carboxylates and Cinchona Alkaloids (2010)
  • Author(s): H.Saito, et al
  • Journal Title: Heterocycles Volume: 81 Pages: 1149-1155
  • Peer Reviewed
• [Journal Article] Catalytic Asymmetric Construction of the 7-exo-Aryl-6,8-dioxabicyclo[3.2.1]octane Framework of Psoracorylifols B and C Using a Carbonyl Ylide Cycloaddition Strategy (2010)
  • Author(s): Y.Kurosaki, et al
  • Journal Title: Bulletin of the Korean Chemical Society Volume: 31 Pages: 694-696
  • Peer Reviewed
• [Journal Article] Catalytic Asymmetric Synthesis of the endo-6-Aryl-8-oxabicyclo[3.2.1]oct-3-en-2-one Natural Product from Ligusticum Chuanxing via 1,3-Dipolar Cycloaddition of a Formyl-Derived Carbonyl Ylide Using Rh_2(S-TCPTTL)_4 (2010)
  • Author(s): N.Shimada, et al
  • Journal Title: Journal of Organic Chemistry Volume: 75 Pages: 6039-6042
  • Peer Reviewed
• [Journal Article] Catalytic Asymmetric Synthesis of Descurainin via 1,3-Dipolar Cycloaddition of a Carbonyl Ylide using Rh_2(R-TCPTTL)_4 (2010)
  • Author(s): N.Shimada, et al
  • Journal Title: Tetrahedron Letters Volume: 51 Pages: 6572-6575
  • Peer Reviewed
• [Journal Article] Stereocontrolled Construction of 1,2-cis-α-Glycosidic Linkages Using Glycosyl Diphenyl Phosphates and Synthesis of α-galactosylceramide KRN7000 (2010)
  • Author(s): H.Nambu, et al
  • Journal Title: Trends Glycosci.Glycotechnol Volume: 22 Pages: 26-40
  • Peer Reviewed
• [Journal Article] A Short Catalytic Asymmetric Synthesis of Diospongins A and B via a One-pot Sequential Hetero-Diels-Alder/Mukaiyama-Michael Reaction Process (2010)
  • Author(s): M.Anada, et al
  • Journal Title: European Journal of Organic Chemistry Pages: 6850-6854
  • Peer Reviewed
• [Journal Article] The Mukaiyama Aldol and Mukaiyama-Michael Reaction Promoted by Commercially Available Molecular Sieves (2010)
  • Author(s): M.Anada, et al.
  • Journal Title: Heterocycles Volume: 80(2) Pages: 1489-1503
  • NAID: 40016991509
  • Peer Reviewed
• [Journal Article] Asymmetric Formal Synthesis of (-)-Pancracine via Catalytic Enantioselective C-H Amination Process (2009)
  • Author(s): M.Anada, et al.
  • Journal Title: Tetrahedron Volume: 65(16) Pages: 3069-3077
  • Peer Reviewed
• [Journal Article] Enantioselective Construction of 2,8-Dioxabicyclo[3.2.1]octane Ring System via [2,3]-Sigmatropic Rearrangement of Oxonium Ylide Using Chiral Dirhodium(II) Carboxylates (2009)
  • Author(s): N.Shimada, et al.
  • Journal Title: Chemistry Letters Volume: 38(5) Pages: 488-489
  • Peer Reviewed
• [Journal Article] Asymmetric Synthesis of Neolignans (-)-epi-Conocarpan and (+)-Conocarpan via Rh(II)-Catalyzed C-H Insertion Process and Revision of the Absolute Configuration of (-)-epi-Conocarpan (2009)
  • Author(s): Y.Natori, et al.
  • Journal Title: The Journal of Organic Chemistry Volume: 74(11) Pages: 4418-4421
  • Peer Reviewed
• [Journal Article] Highly Enantioselective Hetero-Diels-Alder Reactions between Rawal's Diene and Aldehydes Catalyzed by Chiral Dirhodium(II) Carboxamidates (2009)
  • Author(s): Y.Watanabe, et al.
  • Journal Title: Chemical Communications Volume: (47) Pages: 7294-7296
  • Peer Reviewed
• [Journal Article] Direct and Stereoselective Synthesis of 2-Azido-2-deoxy-β-D-Mannosides Using the Phosphate Method (2009)
  • Author(s): S.Nakamura, et al.
  • Journal Title: Heterocycles Volume: 77(2) Pages: 843-848
  • Peer Reviewed
• [Presentation] Highly Enantioselective Cyclopropenation Reaction of 1-Alkynes with α-Alkyl-α- diazoesters Catalyzed by Dirhodium(II) Carboxylates (2012)
  • Author(s): Hashimoto, S.
  • Organizer: BIT’s 3rd Annual World Congress of Catalytic Asymmetric Synthesis 2012
  • Place of Presentation: Beijing International Convention Center, China
  • Year and Date: 2012-05-12
• [Presentation] 二核Rh(II)錯体を用いる触媒的不斉環形成反応 (2010)
  • Author(s): 橋本俊一
  • Organizer: 日本プロセス化学会2010サマーシンポジウム
  • Place of Presentation: タワーホール船堀(東京)(招待講演)
  • Year and Date: 2010-07-16
• [Presentation] Catalytic Asymmetric Reactions Using Chiral Rh(II) Complexes (2010)
  • Author(s): 橋本俊一
  • Organizer: Symposium on Molecular Chirality 2010
  • Place of Presentation: 札幌コンベンションセンター(北海道)(招待講演)
  • Year and Date: 2010-07-12
• [Presentation] 高選択的合成反応の開発と生物活性物質の合成
  • Author(s): 橋本俊一
  • Organizer: 第27回創薬セミナー
  • Place of Presentation: 信州松代ロイヤルホテル（長野）
  • Invited
• [Presentation] 二核ロジウム(II)錯体を用いた触媒的不斉合成反応
  • Author(s): 橋本俊一
  • Organizer: 第7回北里化学シンポジウム
  • Place of Presentation: 北里大学（東京）
  • Invited
• [Presentation] 二核ロジウム(II)錯体を用いた触媒的不斉合成反応
  • Author(s): 橋本俊一
  • Organizer: 塩野義製薬株式会社 医薬研究センター講演会
  • Place of Presentation: 塩野義製薬（大阪）
  • Invited
• [Presentation] 二核ロジウム(II)錯体の創製を基盤とする触媒的不斉合成反応
  • Author(s): 橋本俊一
  • Organizer: 金沢大学薬学シンポジウム2011
  • Place of Presentation: 金沢大学（金沢）
  • Invited