Efficient Synthesis of Biologically Active Natural Products Useful for Drug Discovery

• Project/Area Number: 22249001
• 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, 教授 (20143000)
• Co-Investigator(Kenkyū-buntansha): ISHIHARA Jun 長崎大学, 医歯薬学総合研究科, 准教授 (80250413) ; TAKAHASHI Keisuke 長崎大学, 医歯薬学総合研究科, 助教 (60380854)
• Project Period (FY): 2010 – 2012
• Project Status: Completed (Fiscal Year 2012)
• Budget Amount: ¥49,140,000 (Direct Cost: ¥37,800,000、Indirect Cost: ¥11,340,000); Fiscal Year 2012: ¥10,270,000 (Direct Cost: ¥7,900,000、Indirect Cost: ¥2,370,000); Fiscal Year 2011: ¥14,430,000 (Direct Cost: ¥11,100,000、Indirect Cost: ¥3,330,000); Fiscal Year 2010: ¥24,440,000 (Direct Cost: ¥18,800,000、Indirect Cost: ¥5,640,000)
• Keywords: 全合成 / 天然物 / オキサゾロマイシン / ウエルウィスタチン / カイトセファリン / オキゾロマイシン

Research Abstract

We have studied on the total synthesis of natural products having intriguing biological activities useful for drug discovery. As a result, we have achieved the total syntheses of oxazolomycin A and kitocephalin, and the formal synthesis of welwistatin. In addition, we have developed a new methodology for the construction of heterocycles which relies on a Rh(II)-catalyzed C-H amination reaction, and have achieved the total syntheses of NW-G01, englerin A, and inthomycin A, B, C.

Research Products

• [Journal Article] Organocatalytic Asymmetric Syntheses of Inthomycins A, B and C (2012)
  • Author(s): Madoka Yoshino, Kohei Eto, Keisuke Takahashi, Jun Ishihara, Susumi Hatakeyama
  • Journal Title: Org. Biomol. Chem. Volume: 10 Issue: 40 Pages: 8164-74
  • DOI: 10.1039/c2ob26084k
  • Peer Reviewed
• [Journal Article] Stereocontrolled Total Synthesis of (-)-Englerin A (2012)
  • Author(s): Keisuke Takahashi, Keita Komine, Yuichi Yokoi, Jun Ishihara, Susumi Hatakeyama
  • Journal Title: J. Org. Chem Volume: 77 Issue: 17 Pages: 7364-70
  • DOI: 10.1021/jo301145r
  • Peer Reviewed
• [Journal Article] Total Synthesis of (-)-Kaitocephalin Based on a Rh-Catalyzed C-H Amination (2012)
  • Author(s): Keisuke Takahashi
  • Journal Title: Organic Letters Volume: VOL.14 Issue: 6 Pages: 1644-1647
  • DOI: 10.1021/ol300431n
  • Peer Reviewed
• [Journal Article] Sereoselective Synthesis of the Fused γ-Lactone/δ-Lactone Core of Ophiodilactones (2012)
  • Author(s): Takaaki Matsubara, Keisuke Takahashi, Jun Ishihara, Susumi Hatakeyama
  • Journal Title: Heterocycles Volume: 86 Issue: 1 Pages: 155-158
  • DOI: 10.3987/com-12-s(n)46
  • Peer Reviewed
• [Journal Article] Recent Developments in the Reformatsky-Claisen Rearrangement (2012)
  • Author(s): Jun Ishihara, Susumi Hatakeyama
  • Journal Title: Molecules Volume: 17 Issue: 12 Pages: 14249-14259
  • DOI: 10.3390/molecules171214249
  • Peer Reviewed
• [Journal Article] A New Method for the Protection of Carboxylic Acids with a Triisopropylsiloxymethyl Group (2012)
  • Author(s): Hikaru Yoshimura, Kohei Eto, Keisuke Takahashi, Jun Ishihara, Susumi Hatakeyama
  • Journal Title: Chemical and Pharmaceutical Bulletin Volume: 60 Issue: 10 Pages: 1334-1339
  • DOI: 10.1248/cpb.c12-00490
  • NAID: 130001852365
  • ISSN: 0009-2363, 1347-5223
  • Peer Reviewed
• [Journal Article] Process Development for the Practical Production of Eldecalcitol by Linear, Convergent and Biomimetic Syntheses (2012)
  • Author(s): Noboru Kubodera
  • Journal Title: Anticancer Research Volume: VOL.32 Pages: 303-310
  • Peer Reviewed
• [Journal Article] Total synthesis of oxazolomycin A : Ore Lett (2011)
  • Author(s): Eto K, et al
  • Journal Title: Organic Letters Volume: VOL.13 Issue: 19 Pages: 5398-5401
  • DOI: 10.1021/ol202306d
  • Peer Reviewed
• [Journal Article] Total synthesis of NW-G01, a cyclic hexapeptide antibiotic, and 34-epi-NW-G01 (2011)
  • Author(s): Shibahara S, et al
  • Journal Title: Organic Letters Volume: VOL.13 Issue: 17 Pages: 4700-4703
  • DOI: 10.1021/ol201912w
  • Peer Reviewed
• [Journal Article] Organocatalytic asymmetric synthesis of quinine and quinidine (2011)
  • Author(s): Shaheen M S, et al
  • Journal Title: Tetrahedron Lett Volume: VOL.52 Issue: 8 Pages: 923-927
  • DOI: 10.1016/j.tetlet.2010.12.066
  • Peer Reviewed
• [Journal Article] Indium-mediated Reformatsky-Claisen rearrangement (2011)
  • Author(s): Jun Ishihara
  • Journal Title: Tetrahedron Volume: VOL.67 Pages: 3659-3667
  • Peer Reviewed
• [Journal Article] Synthesis of 1-deoxyeldecalcitol, a biologically interesting analog of 1α,25-dihydroxy-2β-(3-hydroxypropoxy)vitamin D_3 (eldecalcitol) (2011)
  • Author(s): Sasaki H, et al
  • Journal Title: Heterocycles Volume: VOL.63 Issue: 6 Pages: 1385-1394
  • DOI: 10.3987/com-11-12189
  • Peer Reviewed
• [Journal Article] Organocatalytic Asymmetric Synthesis of Quinine and Quinidine (2011)
  • Author(s): Shaheen M.Sarkar
  • Journal Title: Tetrahedron Letters Volume: VOL.52 Pages: 923-927
  • Peer Reviewed
• [Journal Article] Indium-catalyzed Conia-ene Reaction and Total Syntheses of Biologically Active Alkaloids (2010)
  • Author(s): Keisuke Takahashi, Susumi Hatakeyama
  • Journal Title: Journal of Synthetic Organic Chemistry, Japan Volume: 68 Issue: 9 Pages: 951-961
  • DOI: 10.5059/yukigoseikyokaishi.68.951
  • NAID: 10026870830
  • ISSN: 0037-9980, 1883-6526
  • Peer Reviewed
• [Journal Article] インジウムトリフラートを触媒とするConia-エン反応と生物活性アルカロイドの合成 (2010)
  • Author(s): 高橋圭介
  • Journal Title: 有機合成化学協会誌 Volume: 68巻 Pages: 951-961
  • NAID: 10026870830
  • Peer Reviewed
• [Journal Article] Synthetic Study on Clutiolide Based on a Remote Chelation Controlled Ireland-Claisen Rearrangement (2010)
  • Author(s): Jun Ishihara
  • Journal Title: Heterocycles Volume: VOL.80 Pages: 1067-1079
  • NAID: 40016991478
  • Peer Reviewed
• [Presentation] α-lsocupreine, an Enantiocomplementary Catalyst of β-lsocupreidine (2012)
  • Author(s): Susumi Hatakeyama
  • Organizer: First Japan-USA Organocatalytic Symposium
  • Place of Presentation: Hawaii (USA)
  • Year and Date: 2012-12-17
• [Presentation] New Entryto Substituted Pyrrolidines Based on a Rh-Catalyzed C-H Amination: Synthesis ofKaitocephalin (2012)
  • Author(s): Keisuke Takahashi, Disuke Yamaguchi, Jun Ishihara, Susumi Hatakeyama
  • Organizer: The 12th International Kyoto Conference on New Aspects of Organic Chemistry (IKCOC-12)
  • Place of Presentation: Kyoto (Japan)
  • Year and Date: 2012-11-14
• [Presentation] Welwitindolinone アルカロイドの合成研究 (2012)
  • Author(s): 小嶺敬太,野村祐介,Cyril Pieri,高橋圭介,石原 淳,畑山 範
  • Organizer: 第38回反応と合成の進歩シンポジウム
  • Place of Presentation: 東京
  • Year and Date: 2012-11-07
• [Presentation] ラジョラマイシンの合成研究 (2012)
  • Author(s): 江藤 康平,高橋圭介,石原 淳,畑山 範
  • Organizer: 第42回複素環化学討論会
  • Place of Presentation: 京都
  • Year and Date: 2012-10-13
• [Presentation] Claisen Rearrangement Mediated by Indium Chloride (2011)
  • Organizer: 22nd French-Japanese Symposium of Medicinal and Fine Chemistry
  • Place of Presentation: Rouen (France)
  • Year and Date: 2011-12-12
• [Presentation] Organocatalytic Asymmetric Synthesis of Inthomycin A, B and C (2011)
  • Author(s): Kohei Eto, Madoka Yoshino, Keisuke Takahashi, Jun Ishihara, Susumi Hatakeyama
  • Organizer: 8th AFMC International Medicinal Chemistry Symposium
  • Place of Presentation: Tokyo (Japan)
  • Year and Date: 2011-12-02
• [Presentation] Organocatalytic Asymmetric Synthesis of Inthomycin A, B and C (2011)
  • Author(s): Kohei Eto
  • Organizer: 8th AFMC International Medicinal Chemistry Symposium
  • Place of Presentation: Keio Plaza Hotel (Tokyo)
  • Year and Date: 2011-12-02
• [Presentation] エングレリンA の全合成 (2011)
  • Author(s): 高橋圭介,横井裕一,小嶺敬太,石原 淳,畑山 範
  • Organizer: 第37回反応と合成の進歩シンポジウム
  • Place of Presentation: 徳島
  • Year and Date: 2011-11-07
• [Presentation] C-Hアミノ化を基盤とするカイトセファリンの全合成研究 (2011)
  • Author(s): 高橋圭介,山口大介,Lu Shenlei,石原淳,畑山 範
  • Organizer: 第53回天然有機化合物討論会
  • Place of Presentation: 大阪
  • Year and Date: 2011-09-29
• [Presentation] C-Hアミノ化を基盤とするカイトセファリンの全合成研究 (2011)
  • Author(s): 高橋圭介
  • Organizer: 第53回天然有機化合物討論会
  • Place of Presentation: 大阪国際センター(大阪市)
  • Year and Date: 2011-09-29
• [Presentation] Total Synthesis of Chloptosin (2010)
  • Author(s): Setsuya Shibahara, Takaaki Matsubara, Keishke Takahashi, Jun Ishihara, Susumi Hatakeyama
  • Organizer: The 2010 International Chemical Congressof Pacific Basin Societies
  • Place of Presentation: Hawaii (USA)
  • Year and Date: 2010-12-19
• [Presentation] Synthetic study on the oxazolomycin family of compounds (2010)
  • Author(s): Kohei Eto
  • Organizer: Pacifichem 2010
  • Place of Presentation: Convention Center (Honolulu)
  • Year and Date: 2010-12-19
• [Presentation] ピロロインドリン含有環状ヘキサペプチド類の合成研究 (2010)
  • Author(s): 芝原攝也,松原孝昌,高橋圭介,石原 淳,畑山 範
  • Organizer: 第36回反応と合成の進歩シンポジウム
  • Place of Presentation: 名古屋
  • Year and Date: 2010-11-02
• [Presentation] インソマイシン及びオキサゾロマイシン類抗生物質の合成研究 (2010)
  • Author(s): 江藤康平,吉野円香,高橋圭介,石原 淳,畑山 範
  • Organizer: 第52回天然有機化合物討論会
  • Place of Presentation: 静岡
  • Year and Date: 2010-10-01
• [Presentation] インソマイシン及びオキサゾロマイシン類抗生物質の合成研究 (2010)
  • Author(s): 江藤康平
  • Organizer: 第52回天然有機化合物討論会
  • Place of Presentation: グランシップ(静岡市)
  • Year and Date: 2010-10-01
• [Presentation] New Variant of Reformasky
  • Author(s): Jun Ishihara, Yuki Watanabe, NorikoKoyama, Yukihiro Nishino, Keisuke Takahashi, Susumi Hatakeyama
• [Presentation] オフィオジラクトン天然物の全合成研究
  • Author(s): 松原孝昌、高橋圭介、石原淳、畑山範
  • Organizer: 第54回天然有機化合物討論会
  • Place of Presentation: 東京農業大学（東京都）
• [Presentation] Welwitindolinoneアルカロイドの合成研究
  • Author(s): 小嶺敬太、野村祐介、Cyril Pieri、高橋圭介、石原淳、畑山範
  • Organizer: 第38回反応と合成のシンポシンポジウム
  • Place of Presentation: タワーホール船橋（東京都）
• [Presentation] New Entry to Substituted Pyrrolidines Based on a Rh-Catalyzed C-H Amination: Synthesis of Kaitocephalin
  • Author(s): Keisuke Takahashi, Daisuke Yamaguchi, jun Ishihara, Susumi Hatakeyama
  • Organizer: The 12th International Kyoto Conference on New Aspects of Organic Chemistry (IKCOC-12)
  • Place of Presentation: Rihga Royal Hotel Kyoto (Kyoto)
• [Presentation] α-Isocupreine, an Enantiocomplementary Catalyst of β-Isocupreidine
  • Author(s): Susumi Hatakeyama
  • Organizer: Fiest Japan-USA Organocataltic Symposium
  • Place of Presentation: Waikiki Prince Hotel（Hawaii）
  • Invited
• [Book] Science of Synthesis, Asymmetric Organocatalysis 1 Lewis Base and Acid Catalysts (2012)
  • Author(s): Susumi Hatakeyama
  • Publisher: Georg Thieme Verlarg KG
• [Book] Science of Synthesis: Asymmetric Organocatalysis 1 Lewis Base and Acid Catalysis (2011)
  • Author(s): Susumi Hatakeyama
  • Publisher: Benjamin List Ed.; Georg Thieme Verlag: New York
• [Book] 天然物合成で活躍した反応-実験のコツとポイント(有機合成化学協会 編) (2011)
  • Author(s): 畑山 範,高橋圭介
  • Publisher: 化学同人
• [Remarks]
  • URL: http://www.ph.nagasaki-u.ac.jp/lab/manufac/index-j.html
• [Remarks]
  • URL: http://www.ph.nagasaki-u.ac.jp/lab/manufac/index-j.html
• [Patent(Industrial Property Rights)] 新規キノリン誘導体およびこれを含有する有機触媒 (2012)
  • Inventor(s): 畑山 範、石原 淳、高橋圭介、中本義人
  • Industrial Property Rights Holder: 長崎大学
  • Industrial Property Number: 2012-253343
  • Filing Date: 2012-11-19
  • Overseas
• [Patent(Industrial Property Rights)] 新規キノリン誘導体 およびこれを含有する 有機触媒 (2012)
  • Inventor(s): 畑山範、石原淳、高橋圭介、中本義人
  • Industrial Property Rights Holder: 長崎大学
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2012-253343
  • Filing Date: 2012-11-19