単一不斉触媒による連続不斉中心構築法を基盤とする有用生物活性化合物の効率的合成

• Project/Area Number: 17689002
• Research Category: Grant-in-Aid for Young Scientists (A)
• Allocation Type: Single-year Grants
• Research Field: Chemical pharmacy
• Research Institution: Osaka University
• Principal Investigator: 大嶋 孝志 Osaka University, 大学院・基礎工学研究科, 准教授 (10313123)
• Project Period (FY): 2005 – 2007
• Project Status: Completed (Fiscal Year 2007)
• Budget Amount: ¥30,030,000 (Direct Cost: ¥23,100,000、Indirect Cost: ¥6,930,000); Fiscal Year 2007: ¥7,800,000 (Direct Cost: ¥6,000,000、Indirect Cost: ¥1,800,000); Fiscal Year 2006: ¥9,750,000 (Direct Cost: ¥7,500,000、Indirect Cost: ¥2,250,000); Fiscal Year 2005: ¥12,480,000 (Direct Cost: ¥9,600,000、Indirect Cost: ¥2,880,000)
• Keywords: 連続不斉中心構築 / 多段階連続反応 / 触媒的不斉反応 / Michael反応 / Mannich型反応 / アルキニル化反応 / アミノ化反応 / 環境調和性 / 金属クラスター / オキサゾリン / アミド化反応 / Cylindricine C / Aldol反応 / エポキシ化反応

Research Abstract

医薬品やその研究開発に必要な有用生物活性化合物を、大量にしかも地球環境に負荷をかけることなく実用的に供給する方法を開発することを目的とし、「単一不斉触媒による連続不斉中心構築法」の開発および「有用生物活性化合物の効率的合成」への展開の検討を行った。(1)先に我々が開発した不斉相問移動触媒TaDiASを触媒ニよるとして用いる不斉Michael反応と、立体選択的多段階の環化反応を鍵反応として用いることで,Cylindricine C短工程合成ルートを開発することに成功した。今回、環化反応の立体選択性を逆転させることに成功しLepadiformineの短工程形式不斉合成を達成した。また、第3世代のTaDiAS触媒を用いることで、不斉Mannich型反応の選択性を向上させることに成功し、抗精神病薬Nemonaprideの効率的不斉合成法の開発を達成した。(2)In触媒によるアルキニル化反応において、ビフェノール型の配位子が反応性を大幅に加速化することを見いだした。また、求核剤として新たにアセチレンのアセトン付加体を用いる反応条件を確立し、合成化学的に有用な様々な光学活性プロパルギルアルコールを高い不斉収率(最高99%ee)で合成できるようになった。(3)アリルアルコールを直接接用いる、触媒的なアミノ化反応を促進する白金触媒系を開発することに成功した。本反応は、従来の方法で必要であった等モル量以上の試薬を用いる基質の活性化が必要でなく、共生成物は水飲みという環境調和性の高い触媒反応である。本触媒反応はモノアリル化体を選択的に合成できるという特徴を有しており、また、本触媒反応を用いることで抗真菌薬naftifineの1工程合成法の開発にも成功した。

Research Products

• [Journal Article] Enzyme-like Clienioselective Acylation of Alcohols in the presence of Amines Catalyzed by a Tetranuclear Zinc Cluster. (2008)
  • Author(s): T. Ohshima, et. al.
  • Journal Title: J. Am. Chem. Soc. 130 Pages: 2944-2945
  • Peer Reviewed
• [Journal Article] Highly Enantio- and s-trans, C-C Double Bond Selective Catalytic Hydrogenation of Cyclic Enones: Alternative Synthesis of (-)-Menthol (2008)
  • Author(s): T. Ohshima, et. al.
  • Journal Title: Chem. Eur. J. 14 Pages: 2060-2066
  • Peer Reviewed
• [Journal Article] Novel Ir-SYNPHOS^(R) and lr-DIFLUORPHOS^(R) Catalysts for Asymmetric Hydrogenation of Quinolines (2007)
  • Author(s): C. Deport, et. al.
  • Journal Title: Synlett Pages: 2743-2747
  • Peer Reviewed
• [Journal Article] Direct Use of Allylic Alcohols for Platinum- Catalyzed Monoallylation of Amines (2007)
  • Author(s): M.Utsunomiya, et. al.
  • Journal Title: Org. Lett. 9 Pages: 3371-3374
  • Peer Reviewed
• [Journal Article] Catalytic Asymmetric Phase-Transfer Michael reaction and Mannich-type Eeaction of Glycine Schiff Base with Chiral Two-Center Organocatalyst (2007)
  • Author(s): T. Shibuguchi, et. al.
  • Journal Title: Chem. Asia. J. 2 Pages: 794-801
  • Peer Reviewed
• [Journal Article] Short Synthesis of (+)-Cylindricine C and Formal Total Synthesis of (-)-Lepadiformine (2007)
  • Author(s): H. Miiara, et. al.
  • Journal Title: Heterocycles 72 Pages: 421-438
  • Peer Reviewed
• [Journal Article] Iigand accelerated indium (III)-catalyzed asymmetric alkynylation of aidehydes with 2-methyl-3-butyn-2-ol as an ethyne equivalent donor (2007)
  • Author(s): S. Harada, et. al.
  • Journal Title: Chem. Commun. Pages: 948-450
  • Peer Reviewed
• [Journal Article] Catalytic Asyinmetnc Epoxidation of α,β-Unsatvirated Esters Using Chiral Yttrium-Biaryldiol Complexes (2007)
  • Author(s): H. Kakei, et. al.
  • Journal Title: Chem. Asian. J. 2 Pages: 257-264
  • Peer Reviewed
• [Journal Article] Catalytic Asymmetric Epoxidation of α,β-Unsaturated Esters Using Chiral Yttrium-Biaryldiol Complexes (2007)
  • Author(s): H.Kakei et al.
  • Journal Title: Chem. Asian. J. 2 Pages: 257-264
• [Journal Article] Ligand accelerated indium(III)-catalyzed asymmetric alkynylation of aldehydes with 2-methyl-3-butyn-2-ol as an ethyne equivalent donor (2007)
  • Author(s): S.Harada et al.
  • Journal Title: Chem. Commun. Pages: 948-950
• [Journal Article] SHORT SYNTHESIS OF (+)-CYLINDRICINE C AND FORMAL TOTAL SYNTHESIS OF (-)-LEPADIFORMINE (2007)
  • Author(s): H.Mihara et al.
  • Journal Title: Heterocycles (in press)
• [Journal Article] Direct Conversion of Esters, Lactones, and Carboxylic Acids to Oxazolines Catalyzed by Tetranuclear Zinc Cluster (2006)
  • Author(s): T.Ohshima et al.
  • Journal Title: Chem. Commun. Pages: 2711-2713
• [Journal Article] Short Synthesis of (+)-Cylindricine C Using Catalytic Asymmetric Michael Reaction with a Newly Designed Two-Center Organocatalyst (2006)
  • Author(s): T.Shibuguchi et al.
  • Journal Title: Angew. Chem. Int. Ed. 45 Pages: 4635-4637
• [Journal Article] Hexapalladium cluster : Unique cluster construction reaction of cyclic Pd_3(CNC_6H_3Me_2-2,6)_6 and linear [Pd_3(CNC_6H_3Me_2-2,6)8]^<2+> (2006)
  • Author(s): M.Ohashi et al.
  • Journal Title: J. Organometal. Chem. 691 Pages: 2457-2464
• [Journal Article] Synthesis of the Tricyclic Core of 5α-Capnellenols Using Asymmetric Heck Reaction -Carbanion Capture Process (2006)
  • Author(s): W.Itano et al.
  • Journal Title: Synlett Pages: 3053-3056
• [Journal Article] Dynamic Ligand Exchange of the Lanthanide Complex Leading to Structural and Functional Transformation : One-Pot Sequential Catalytic Asymmetric Epoxidation-Regioselective Epoxide Opening Process (2005)
  • Author(s): Tosaki, S.-y.et al.
  • Journal Title: J.Am.Chem.Soc. 127 Pages: 2147-2155
• [Journal Article] Enantio- and Diastereoselective Catalytic Mannicn-Type Reaction of a Glycine Schiff Base Using a Chiral Two-Center Phase-Transfer Catalyst (2005)
  • Author(s): Okada, A. et al.
  • Journal Title: Angew.Chem.Int.Ed. 44 Pages: 4564-4567
• [Journal Article] A New Entry in Catalytic Alkynylation of Aldehydes and Ketones : Dual Activation of Soft Nucleophiles and Hard Electrophiles by an Indium(III) Catalyst (2005)
  • Author(s): Takita, R. et al.
  • Journal Title: Org.Lett. 7 Pages: 1363-1366
• [Journal Article] Formal Total Synthesis of (+)-Wortmannin Using Catalytic Asymmetric Intramolecular Aldol Condensation Reaction (2005)
  • Author(s): Shigehisa, H. et al.
  • Journal Title: Tetrahedron 61 Pages: 5057-5065
• [Journal Article] Catalytic Asymmetric Epoxidation of α,β-Unsaturated Esters Using an Yttrium-Biphenyldiol Complex (2005)
  • Author(s): Kakei, H. et al.
  • Journal Title: J.Am.Chem.Soc. 127 Pages: 8962-9863
• [Journal Article] Enantio- and diastereoselective construction of vicinal quaternary and tertiary carbon centers by catalytic Michael reaction of α-substituted β-keto esters to cyclic enones (2005)
  • Author(s): Majima, K. et al.
  • Journal Title: Tetrahedron Lett. 43 Pages: 5377-5381
• [Journal Article] A Topological Isomer of Ferrocene : Theoretical Approach for Transition Metal Complexes with Conjugated All Trans Cyclodecapentaene (2005)
  • Author(s): Nakamura, A. et al.
  • Journal Title: J.Organometal.Chem. 690 Pages: 4373-4375
• [Journal Article] Asymmetric Alkynylation of Aldehydes Catalyzed by an In(III)/BINOL Complex (2005)
  • Author(s): Takita, R. et al.
  • Journal Title: J.Am.Chem.Soc. 127 Pages: 13760-13761
• [Presentation] 亜鉛四核クラスター触媒によるアミノアルコールの水酸基選択的アシル化反応の開発 (2008)
  • Author(s): 岩崎孝紀
  • Organizer: 日本化学会第88春季年会
  • Place of Presentation: 東京
  • Year and Date: 2008-03-28
• [Presentation] 亜鉛四核クラスター触媒を用いたエステル交換反応のアミノエステル誘導体への応用 (2008)
  • Author(s): 前川雄亮
  • Organizer: 日本化学会第88春季年会
  • Place of Presentation: 東京
  • Year and Date: 2008-03-28
• [Presentation] ロジウム錯体によるα-ケトエステルおよびα-ケトイミノエステルの触媒的不斉アルキニル化反応の開発 (2008)
  • Author(s): 柿沼卓宏
  • Organizer: 日本化学会第88春季年会
  • Place of Presentation: 東京
  • Year and Date: 2008-03-28
• [Presentation] 亜鉛四核クラスター触媒によるアミノアルコールの水酸基選択的アシル化反応の開発 (2008)
  • Author(s): 岩崎孝紀
  • Organizer: 日本薬学会第128年会
  • Place of Presentation: 横浜
  • Year and Date: 2008-03-27
• [Presentation] 不斉ロジウム錯体触媒によるエノンの高エナンチオ-、位置選択的不斉水素科反応と(-)-メントール合成への応用 (2008)
  • Author(s): 唯岡弘
  • Organizer: 日本薬学会第128年会
  • Place of Presentation: 横浜
  • Year and Date: 2008-03-27
• [Presentation] 不斉ロジウム触媒による環状エノンの高エナンチオ、位置選択的不斉水素化反応と(一)-メントール合成への応用 (2008)
  • Author(s): 唯岡弘
  • Organizer: 日本化学会第88春季年会
  • Place of Presentation: 東京
  • Year and Date: 2008-03-27
• [Presentation] 金触媒を用いたアリルアルコールの窒素求核剤による直接的置換反応の開発 (2008)
  • Author(s): 一法師純司
  • Organizer: 日本化学会第88春季年会
  • Place of Presentation: 東京
  • Year and Date: 2008-03-26
• [Presentation] 白金触媒によるアリルアルコールの直接的アミノ化反応の最適化 (2008)
  • Author(s): 宮本佳季
  • Organizer: 日本化学会第88春季年会
  • Place of Presentation: 東京
  • Year and Date: 2008-03-26
• [Presentation] 無保護アミノアルコールの触媒的な水酸基選択的アシル化反応の開発 (2008)
  • Author(s): 岩崎孝紀
  • Organizer: 第8回GSCシンポジウム
  • Place of Presentation: 東京
  • Year and Date: 2008-03-06
• [Presentation] 不斉ジホスフィン配位子を有するロジウム錯体によるエノンの不斉水素化反応とメントール合成への応用 (2008)
  • Author(s): 唯岡弘
  • Organizer: 第8回GSCシンポジウム
  • Place of Presentation: 東京
  • Year and Date: 2008-03-06
• [Presentation] Development of Highly Chemoselective 0-Acylation of Aminoalcohols Catalvzed by Tetranuclear Zinc Cluster (2008)
  • Author(s): Takanori Iwasaki
  • Organizer: The 1st International Global COE Symposiuin on Bio-Environmental Chemistry
  • Place of Presentation: 大阪
  • Year and Date: 2008-01-28
• [Presentation] Enantio- and Regioselective Hydrogenation of Enones Catalyzed by Rhodium Comolexes Bearing Chiral Diphosphine Ligand (2008)
  • Author(s): Hiroshi Tadaoka
  • Organizer: The 1st International Global COE Symposium on Bio-Environmental Chemistry
  • Place of Presentation: 大阪
  • Year and Date: 2008-01-28
• [Presentation] 亜鉛クラスターを基軸とする環境調和型触媒反応の開発 (2007)
  • Author(s): 大嶋孝志
  • Organizer: 特定領域研究「協奏機能触媒」第3回公開シンポジウム
  • Place of Presentation: 福岡
  • Year and Date: 2007-12-13
• [Presentation] Direct Conversion of Esters, Lactones, and Carboxylic Acids to Oxazolines Catalyzed by a Tetranuclear Zinc Cluster (2007)
  • Author(s): Takanori Iwasaki
  • Organizer: Green Sustainable Biological and Chemical Processes
  • Place of Presentation: 大阪
  • Year and Date: 2007-11-16
• [Presentation] Development of New Catalytic Transesterification Reaction Using Tetranuclear Zinc Cluster (2007)
  • Author(s): Yusuke Maegaia
  • Organizer: Green Sustainable Biological and Chemical Processes
  • Place of Presentation: 大阪
  • Year and Date: 2007-11-16
• [Presentation] Highly Enantio- and s-trans c-c Double Bond Selective Hydrogenation of Cyclic Enones (2007)
  • Author(s): Hiroshi Tadaoka
  • Organizer: Green Sustainable Biological and Chemical Processes
  • Place of Presentation: 大阪
  • Year and Date: 2007-11-16
• [Presentation] Development of Direct Catalytic Amination of Allylic Alcohols (2007)
  • Author(s): Junji Ipposhi
  • Organizer: The 2n(i International Symposium for Yong Elements Chemists: 2007 Workshop on Organometallic Chemistry
  • Place of Presentation: 埼玉
  • Year and Date: 2007-11-08
• [Presentation] 亜鉛四核クフスター触媒によるエステル結合活性化を鍵とするエステル交換反応の開発 (2007)
  • Author(s): 岩崎孝紀
  • Organizer: 第33回反応と合成の進歩シンポジウム
  • Place of Presentation: 長崎
  • Year and Date: 2007-11-06
• [Presentation] 不斉ロジウム触媒による環状エノンの高エナンチオ、位置選択的水素化反応 (2007)
  • Author(s): 唯岡弘
  • Organizer: 第33回反応と合成の進歩シツポジウム
  • Place of Presentation: 長崎
  • Year and Date: 2007-11-06
• [Presentation] Development ol、New Direct Ami nation of Allylic Alcohols Using Efficient Platinum Catalyst (2007)
  • Author(s): 宮本佳季
  • Organizer: 第54回有機金属化学討論会
  • Place of Presentation: 広島
  • Year and Date: 2007-10-28
• [Presentation] Uevelopment of New Catalytic. Transesterification Reaction Using Tetranuclear Zinc Cluster (2007)
  • Author(s): 前川雄亮
  • Organizer: 弟54回有機金属化学討論会
  • Place of Presentation: 広島
  • Year and Date: 2007-10-27
• [Presentation] アリルアルコールの放課的直接アミノ化反応の開発 (2007)
  • Author(s): 一法師純司
  • Organizer: 第37回復素環化学討論会
  • Place of Presentation: 長野
  • Year and Date: 2007-10-18
• [Presentation] Developient of New Direct Catalytic Reaction Using Zinc Clusters〜Control of Amide Bond and Ester Bond〜 (2007)
  • Author(s): Takashi Ohshima
  • Organizer: 14th IUPAC Symposium on Organometallic Chemistry Directed Toward Organic Synthesis
  • Place of Presentation: 奈良
  • Year and Date: 2007-08-05
• [Presentation] Synthetic studies on 5α-eapnellenols Using Asymmetric Heck Reaction (2007)
  • Author(s): Wataru Itano
  • Organizer: 14th IDPAC Symposium on Organometallic Chemistry Directed Toward Organic Synthesis
  • Place of Presentation: 奈良
  • Year and Date: 2007-08-05
• [Presentation] Development of new catalytic transesterification reaction using tetran uclear zinc cluster (2007)
  • Author(s): 前川雄亮
  • Organizer: First International Conference on Advanced Organic Synthesis Directed toward the Ultimate、Efficiency and Practicability
  • Place of Presentation: 大津
  • Year and Date: 2007-05-28
• [Presentation] Development of New Direct Amination of Allylic Alcohols Using Efficient Platinum Catalyst (2007)
  • Author(s): 宮本佳季
  • Organizer: First International Conference on Advanced Organic Synthesis Directed toward the Ultimate Efficiency and Practicability
  • Place of Presentation: 大津
  • Year and Date: 2007-05-28
• [Book] The Alkaloids (Recent Studies on the Synthesis of Siaycliniiie) (2008)
  • Author(s): M. Stabasaki, T. Ohshima
  • Publisher: Academic Press, New York(印刷準備中)
• [Book] The Heck Reaction (DesyTmnetriziiig Heck Eeactions) (2008)
  • Author(s): M. Shibasaki, T. Ohshima
  • Publisher: WILEY-VCH, Weinheim (印刷準備中)
• [Book] Asymmetric Phase Transfer Catalysis (Two-center Chiral Phase Transfer Catalysts for Asjanmetric Synthesis) (2008)
  • Author(s): M. Shibasaki, T. Ohshima
  • Publisher: WILEY-VCH, Weiaheim (印刷準備中)
• [Book] 「有機分子触媒の新展開」多点認識型有機分子触媒の開発 (2006)
  • Author(s): 柴崎正勝, 大嶋孝志
  • Total Pages: 11
  • Publisher: シーエムシー出版
• [Book] 「ケミカルエンジニアリング」新規触媒的不斉アルキニル化反応の開発 (2006)
  • Author(s): 柴崎正勝, 大嶋孝志
  • Total Pages: 5
  • Publisher: 化学工業社
• [Remarks]
  • URL: http://homepage.mac.com/takashiohshima/
• [Patent(Industrial Property Rights)] 水酸基のアシル化反応 (2007)
  • Inventor(s): 真島和志, 他
  • Industrial Property Rights Holder: 真島和志, 他
  • Industrial Property Number: 2007-265946
  • Filing Date: 2007-10-11
• [Patent(Industrial Property Rights)] 金属触媒による縮合反応 (2005)
  • Inventor(s): 真島和志, 大嶋孝志, 岩崎孝紀
  • Industrial Property Rights Holder: 大阪大学高砂香料
  • Industrial Property Number: 2006-324176
  • Filing Date: 2005-09-20
• [Patent(Industrial Property Rights)] 金属触媒による縮合反応 (2005)
  • Inventor(s): 真島 和志, 大嶋 孝志, 岩崎 孝紀
  • Industrial Property Rights Holder: 大阪大学, 高砂香料
  • Filing Date: 2005-09-20