Efficient Synthesis of Natural Products Useful for Drug Discovery Based on Innovative Synthetic Methodologies

• Project/Area Number: 25253002
• Research Category: Grant-in-Aid for Scientific Research (A)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Chemical pharmacy
• Research Institution: Nagasaki University
• Principal Investigator: HATAKEYAMA Susumi 長崎大学, 医歯薬学総合研究科(薬学系), 教授 (20143000)
• Co-Investigator(Kenkyū-buntansha): ISHIHARA JUN 長崎大学, 医歯薬学総合研究科(薬学系), 准教授 (80250413) ; TAKAHASHI KEISUKE 長崎大学, 医歯薬学総合研究科(薬学系), 助教 (60380854)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥46,670,000 (Direct Cost: ¥35,900,000、Indirect Cost: ¥10,770,000); Fiscal Year 2015: ¥12,350,000 (Direct Cost: ¥9,500,000、Indirect Cost: ¥2,850,000); Fiscal Year 2014: ¥13,520,000 (Direct Cost: ¥10,400,000、Indirect Cost: ¥3,120,000); Fiscal Year 2013: ¥20,800,000 (Direct Cost: ¥16,000,000、Indirect Cost: ¥4,800,000)
• Keywords: 合成化学 / 全合成 / 天然物

Outline of Final Research Achievements

We have studied on the total synthesis of natural products having intriguing structures and biological activities useful for drug discovery. As a result, we have achieved the total syntheses of lajollamycin B and N-methylwelwitindolinone C isothiocyanate. In addition, we have developed a new methodology for tetrahydrofuran synthesis which relies on a Rh(II)/Zn(II)-catalyzed [4 + 1]-cycloaddition reaction of a homopropargyl alcohol, and have achieved the total syntheses of cinatrin C1, ophiodilactones A and B, and marinomycin A.

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
• [Journal Article] Synthesis of Heterocycles Based on a Rh-catalyzed C-H Amination (2014)
  • Author(s): Keisuke Takahashi, Daisuke Yamaguchi, Jun Ishihara, Susumi Hatakeyama
  • Journal Title: Synlett Volume: 25 Issue: 01 Pages: 133-137
  • DOI: 10.1055/s-0033-1340159
  • Peer Reviewed
• [Journal Article] Total Synthesis of (-)-Ophiodilactone A and (-)-Ophiodilactone B (2014)
  • Author(s): Takaaki Matsubara, Keisuke Takahashi, Jun Ishihara, Susumi Hatakeyama
  • Journal Title: Angewandte Chemie International Edition Volume: 53 Issue: 3 Pages: 757-760
  • DOI: 10.1002/anie.201307835
  • Peer Reviewed
• [Journal Article] Formal [4 + 1]-Cycloaddition of Homopropargyl Alcohols to Diazo Dicarbonyl Compounds Giving Substituted Tetrahydrofurans (2014)
  • Author(s): Fumiya Urabe, Shohei Miyamoto, Keisuke Takahashi, Jun Ishihara, Susumi Hatakeyama
  • Journal Title: Organic Letters Volume: 16 Issue: 3 Pages: 1004-1007
  • DOI: 10.1021/ol403746r
  • Peer Reviewed
• [Journal Article] Total Synthesis of (-)-Cinatrin C-1 Based on an In(OTf)(3)-Catalyzed Conia-Ene Reaction (2013)
  • Author(s): Urabe, Fumiya; Nagashima, Shunsuke; Takahashi, Keisuke;Ishihara, Jun; Hatakeyama Susumi
  • Journal Title: JOURNAL OF ORGANIC CHEMISTRY Volume: 78 Issue: 8 Pages: 3847-3857
  • DOI: 10.1021/jo400263w
  • Peer Reviewed
• [Journal Article] Total Synthesis of (－)-Cinatrin C1 Based on an In(OTf)3-Catalyzed Conia-Ene Reaction (2013)
  • Author(s): Fumiya Urabe, Shunsuke Nagashima, Keisuke Takahashi, Jun Ishihara, Susumi Hatakeyama
  • Journal Title: The Journal of Organic Chemistry Volume: 78 Issue: 38 Pages: 3847-3857
  • DOI: 10.1002/chem.201302665
  • Peer Reviewed
• [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: 2015-12-19
  • 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: 2015-11-19
• [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] 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
• [Presentation] 二量化アプローチによるマリノマイシンＡの効率的不斉全合成 (2014)
  • Author(s): 西丸達也、近藤維志、竹下公人、高橋圭介、石原淳、畑山範
  • Organizer: 第24回万有福岡シンポジウム
  • Place of Presentation: 福岡市、九州大学医学部百年講堂
  • Year and Date: 2014-06-07
• [Presentation] New Pyrrolidine Synthesis Based on a Rh-catalyzed C-H Amination: Total Synthesis of Kaitocephalin (2013)
  • Author(s): Susumi Hatakeyama
  • Organizer: The 15th Asian Chemical Congress (15ACC)
  • Place of Presentation: Singapore, Resorts World Sentosa
  • Invited
• [Presentation] 不斉有機触媒を活用する天然物合成 (2013)
  • Author(s): 畑山 範
  • Organizer: 第30回有機合成化学セミナー
  • Place of Presentation: 倉敷市、せとうち児島ホテル
  • Invited
• [Presentation] Welwistatinの全合成研究 (2013)
  • Author(s): 小嶺敬太、野村祐介、Cyril Pieri、高橋圭介、石原 淳、畑山 範
  • Organizer: 第43回複素環化学討論会
  • Place of Presentation: 岐阜市、長良川国際会議場
• [Presentation] α-Isocupreine, a New Cinchona Alkaloid Catalyst (2013)
  • Author(s): Susumi Hatakeyama
  • Organizer: The 11th International Symposium on Organic Reaction (ISOR-11)
  • Place of Presentation: Taipei, Howard International House
  • Invited
• [Presentation] アルカロイド合成の新戦略：その発想と展開
  • Author(s): 畑山 範
  • Organizer: 第23回万有福岡シンポジウム
  • Place of Presentation: 福岡市、九州大学医学部百年講堂
  • Invited
• [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