新規シンコナアルカロイド不斉触媒の創製と創薬リード天然物の実践的合成

• Project Area: Advanced Molecular Transformations by Organocatalysts
• Project/Area Number: 26105747
• 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: Nagasaki University
• Principal Investigator: 畑山 範 長崎大学, 医歯薬学総合研究科(薬学系), 教授 (20143000)
• Project Period (FY): 2014-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥6,760,000 (Direct Cost: ¥5,200,000、Indirect Cost: ¥1,560,000); Fiscal Year 2015: ¥3,380,000 (Direct Cost: ¥2,600,000、Indirect Cost: ¥780,000); Fiscal Year 2014: ¥3,380,000 (Direct Cost: ¥2,600,000、Indirect Cost: ¥780,000)
• Keywords: 有機触媒 / 不斉反応 / シンコナアルカロイド

Outline of Annual Research Achievements

本研究では、最近開発したα-イソクプレイン (α-ICPN) を誘導体化し、β-イソクプレイジン (β-ICD) と相補的な触媒能を発揮するent-β-ICD型触媒を新たに創出することを目的としている。また、β-ICDやα-ICPNや関連触媒を活用して、リンパ性フィラリア症の治療薬開発のリードとして期待されるチランダマイシン類天然物とテルモリド類天然物の効率的な合成法の開発を目指している。本年度は、α-ICPNのキノリン部に、Me、n-Bu、およびPh基を導入した誘導体を合成し、ベンズアルデヒドとの森田-Baylis-Hillman反応を指標に触媒活性を調べた。その結果、Me誘導体が良好な収率とエナンチオ選択性を示し (91%、84% ee)、新たなent-β-ICD型触媒を見出すことができた。一方、天然物合成に関しては、β-ICDとα-ICPNを触媒とする不斉森田-Baylis-Hillman反応を活用するポリプロピオナート構造単位の立体制御構築法を確立するとともに、チランダリジジンの初の不斉全合成を達成した。また、テルモリド天然物のC10-C18部の立体制御構築を達成した。

Research Progress Status

27年度が最終年度であるため、記入しない。

Strategy for Future Research Activity

27年度が最終年度であるため、記入しない。

Research Products

• [Journal Article] Total Synthesis of (－)-N-Methylwelwitindolinone C Isothiocyanate Based on a Pd-Catalyzed Tandem Enolate Coupling Strategy (2015)
  • Author(s): Komine, Keita; Nomura, Yusuke; Ishihara, Jun; Hatakeyama, Susumi
  • Journal Title: Organic Letters Volume: 17 (15) Issue: 15 Pages: 3918-3921
  • DOI: 10.1021/acs.orglett.5b01952
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] An enantioselective organocatalyzed aza-Morita－Baylis－Hillman reaction of isatin-derived ketimines with acrolein (2015)
  • Author(s): Y. Yoshida, M. Sako, K. Kishi, H. Sasai, S. Hatakeyama, S. Takizawa
  • Journal Title: Org. Biomol. Chem. Volume: 13 Issue: 34 Pages: 9022-9028
  • DOI: 10.1039/c5ob00874c
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Unified Synthesis of Tirandamycins and Streptolydigins (2015)
  • Author(s): Yoshimura, Hikaru; Takahashi, Keisuke; Ishihara, Jun; Hatakeyama, Susumi
  • Journal Title: Chemical Communications Volume: (51) Issue: 95 Pages: 17004-17007
  • DOI: 10.1039/c5cc07749d
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Stereoselective Approach toward Ophiodilactones Based on an Intramolecular [2+2] Cycloaddition Reaction (2015)
  • Author(s): Takaaki Matsubara, Jun Ishihara, Susumi Hatakeyama
  • Journal Title: Heterocycles Volume: 90 Issue: 1 Pages: 405-424
  • DOI: 10.3987/com-14-s(k)32
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Lewis Acid Template-Catalyzed Asymmetric Diels-Alder Reaction (2015)
  • Author(s): Jun Ishihara, Shino Nakadachi, Yuki Watanabe, Susumi Hatakeyama
  • Journal Title: The Journal of Organic Chemistry Volume: 80 Issue: 4 Pages: 2037-2041
  • DOI: 10.1021/acs.joc.5b00055
  • Peer Reviewed
• [Journal Article] Total Synthesis of (-)-Dihydrosporothriolide Utilizing an Indium-Mediated Reformatsky-Claisen Rearrangement (2014)
  • Author(s): Jun Ishihara, Hiroaki Tsuru, Susumi Hatakeyama
  • Journal Title: J. Org. Chem. Volume: 79 Issue: 12 Pages: 5908-5913
  • DOI: 10.1021/jo5008948
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Total Synthesis of Marinomycin A Based on a Direct Dimerization Strategy (2014)
  • Author(s): Tatsuya Nishimaru, Masashi Kondo, Kimito Takeshita, Keisuke Takahashi, Jun Ishihara, Susumi Hatakeyama
  • Journal Title: Angew. Chem. Int. Ed. Volume: 53 Issue: 32 Pages: 8459-8462
  • DOI: 10.1002/anie.201404408
  • Peer Reviewed
• [Journal Article] The Absolute Configuration for Inthomycin C: Revision of Previously Published Work with a Reinstatement of the (3R)-Configuration for (－)-Inthomycin C (2014)
  • Author(s): Karl J. Hale, Susumi Hatakeyama, Fumiya Urabe, Jun Ishihara, Soraya Manaviazar, Milosz Grabski, Maciej Maczka
  • Journal Title: Organic Letters Volume: 16 Issue: 13 Pages: 3536-3539
  • DOI: 10.1021/ol501484t
  • Peer Reviewed
• [Journal Article] Total Synthesis of Oxazolomycins (2014)
  • Author(s): Jun Ishihara, Susumi Hatakeyama
  • Journal Title: Chem. Rec. Volume: 14 Issue: 4 Pages: 663-677
  • DOI: 10.1002/tcr.201402009
  • Peer Reviewed
• [Journal Article] Total Synthesis of Biologically Active Natural Products Based on Highly Selective Synthetic Methodologies (2014)
  • Author(s): Susumi Hatakeyama
  • Journal Title: Chemical and Pharmaceutical Bulletin Volume: 62 Issue: 11 Pages: 1045-1061
  • DOI: 10.1248/cpb.c14-00474
  • NAID: 130004712908
  • ISSN: 0009-2363, 1347-5223
  • Peer Reviewed / Acknowledgement Compliant
• [Presentation] Synthesis of welwitindolinone alkaloids by Pd(0)-catelyzed intramolecular enolate coupling (2015)
  • Author(s): Keita Komine, Yusuke Nomura, Pieri Cyril, Keisuke Takahashi, Jun Ishihara, Susumi Hatakeyama
  • Organizer: Pacifichem 2015
  • Place of Presentation: Honolulu (USA)、Hilton Hawaiian Village
  • Year and Date: 2015-12-19
  • Int'l Joint Research
• [Presentation] Asymmetric Total Syntheses of Tirandamycins by Utilizing Cinchona Alkaloid Catalyzed Morita-Baylis-Hillman Reactions (2015)
  • Author(s): Hikaru Yoshimura, Keisuke Takahashi, Jun Ishihara, Susumi Hatakeyama
  • Organizer: Pacifichem 2015
  • Place of Presentation: Honolulu (USA)、Hilton Hawaiian Village
  • Year and Date: 2015-12-19
  • Int'l Joint Research
• [Presentation] Total synthesis of marinomycin A based on a direct dimerization strategy (2015)
  • Author(s): Tatsuya Nisimaru, Masash Kondo, Kimito Takeshita, Jun Ishihara, Susumi Hatakeyama
  • Organizer: Pacifichem 2015
  • Place of Presentation: Honolulu (USA)、Hilton Hawaiian Village
  • Year and Date: 2015-12-09
  • Int'l Joint Research
• [Presentation] チランダリジジンの全合成 (2015)
  • Author(s): 吉村 光、高橋圭介、石原 淳、畑山 範
  • Organizer: 第45回複素環化学討論会
  • Place of Presentation: 東京都、早稲田大学国際会議場
  • Year and Date: 2015-11-21
• [Presentation] ラジョラマイシン類天然物の合成研究 (2015)
  • Author(s): 西丸達也、江藤康平、石原 淳、畑山 範
  • Organizer: 第41回反応と合成の進歩シンポジウム
  • Place of Presentation: 東大阪市、近畿大学11月ホール
  • Year and Date: 2015-10-27
• [Presentation] N-Me-Welwitindolinone C isothiocyanateの全合成 (2015)
  • Author(s): 小嶺敬太、野村祐介、高橋圭介、石原 淳、畑山 範
  • Organizer: 第57回天然有機化合物討論会
  • Place of Presentation: 横浜市、神奈川県民ホール
  • Year and Date: 2015-09-08
• [Presentation] Total synthesis of tirandalydigin by utilizing cinchona alkaloid catalyzed Morita-Baylis-Hilmann reactions (2015)
  • Author(s): 吉村 光、高橋圭介、石原 淳、畑山 範
  • Organizer: 第39回内藤コンファレンス
  • Place of Presentation: 札幌市、シャトレーゼガトーキングダム
  • Year and Date: 2015-07-08
• [Presentation] チランダリジジンの合成研究 (2015)
  • Author(s): 吉村光、高橋圭介、石原淳、畑山範
  • Organizer: 日本薬学会第135回年会
  • Place of Presentation: 神戸市、神戸学院大学
  • Year and Date: 2015-03-25 – 2015-03-28
• [Presentation] Organocatalytic Asymmetric Synthesis of Tirandamycins (2014)
  • Author(s): Susumi Hatakeyama
  • Organizer: 第2回有機分子触媒国際会議兼第7回有機触媒シンポジウム
  • Place of Presentation: 東京都、東京大学伊藤謝恩ホール
  • Year and Date: 2014-11-21 – 2014-11-22
  • Invited
• [Presentation] キラルルイス酸テンプレートを触媒とするDiels-Alder反応の開発 (2014)
  • Author(s): 仲達偲乃、川口康徳、渡邊由貴、石原淳、畑山範
  • Organizer: 第40回反応と合成の進歩シンポジウム
  • Place of Presentation: 仙台市、東北大学川内荻ホール
  • Year and Date: 2014-11-10 – 2014-11-11
• [Presentation] チランダマイシン類天然物の不斉全合成 (2014)
  • Author(s): 吉村光、高橋圭介、石原淳、畑山範
  • Organizer: 第56回天然有機化合物討論会
  • Place of Presentation: 高知市、高知県立県民文化ホール
  • Year and Date: 2014-10-15 – 2014-10-17
• [Presentation] Concise Synthesis of Dihydrosporothriolide Utilized by Indium-mediated Refromatsky Claisen Rearrangement (2014)
  • Author(s): Jun Ishihara、Hiroaki Tsuru、Susumi Hatakeyama
  • Organizer: The 24th French-Japanese Symposium on Medicinal and Fine Chemistry (FJS 2014)
  • Place of Presentation: Lyon (France), Faculty of Medicine Lyon RTH Laennec
  • Year and Date: 2014-09-14 – 2014-09-17
• [Remarks] 長崎大学大学院医歯薬学総合研究科 薬品製造化学研究室
  • URL: http://www.ph.nagasaki-u.ac.jp/lab/manufac/index-j.html