多段階促進型不斉触媒反応の創製と有用生物活性化合物合成への展開

• Project/Area Number: 14703032
• Research Category: Grant-in-Aid for Young Scientists (A)
• Allocation Type: Single-year Grants
• Research Field: Chemical pharmacy
• Research Institution: The University of Tokyo
• Principal Investigator: 大嶋 孝志 東京大学, 大学院・薬学系研究科, 助手 (10313123)
• Project Period (FY): 2002 – 2004
• Project Status: Completed (Fiscal Year 2004)
• Budget Amount: ¥28,600,000 (Direct Cost: ¥22,000,000、Indirect Cost: ¥6,600,000); Fiscal Year 2004: ¥7,410,000 (Direct Cost: ¥5,700,000、Indirect Cost: ¥1,710,000); Fiscal Year 2003: ¥9,230,000 (Direct Cost: ¥7,100,000、Indirect Cost: ¥2,130,000); Fiscal Year 2002: ¥11,960,000 (Direct Cost: ¥9,200,000、Indirect Cost: ¥2,760,000)
• Keywords: 多機能不斉触媒 / 多段促進反応 / 触媒的不斉反応 / aldol反応 / Tishchenko反応 / 不斉エポキシ化反応 / 多段階促進反応 / 不斉Michael反応 / N-linked-BINOL / 不斉有機触媒 / 相関移動反応 / α-アミノ酸 / 相間移動反応

Research Abstract

多段階の不斉反応をワンポットで推進する新規多機能不斉触媒の創製と有用生物活性化合物の合成への応用を検討した。
1、アルデヒドとケトンを反応に直接用いることのできる直接的aldol反応は、環境調和の観点から非常に優れた炭素-炭素結合形成反応である。その触媒的不斉反応が柴崎研究室で開発された後、世界中の研究者が精力的に研究を行っているが、依然として基質が限定されており、エチルケトンのようにケトンのα-位にアルキル基を有する基質の適応は困難であった。その主な理由は生成物の不安定さに起因する逆反応の存在であり、今回我々は可逆なaldol反応と非可逆なTishchenko反応を組み合わせることでこの問題を解決し、光学活性な2-アルキル-1,3-ジオール化合物をほぼ完璧なジアステレオ選択性と非常に高いエナンチオ選択性を持って合成することを可能とした。また、本反応のメカニズムを詳細に検討し、希土類錯体にリチウムトリフラートを添加すると、錯体構造が動的に変化することも見いだしている(投稿済み)。
2、不斉希土類錯体を用いるα,β-不飽和アミドの触媒的不斉エポキシ化反応終了後、窒素、硫黄、および炭素求核剤を系中に加えると、より高活性な希土類-求核剤錯体が生成し、ワンポットで様々なβ-置換-α-ヒドロキシアミドが高収率で得られることを見いだした。また、新たな希土類-求核剤錯体の形成をin situ IR測定などを通じて立証することができた。すなわち、希土類錯体は動的に配位子交換を行うことによって、二つの反応それぞれにおいて真の活性種として働いている。また、得られた光学的にほぼ純粋なβ-置換-α-ヒドロキシアミドは数工程の変換によって有用生物活性化合物の合成ユニットに変換することができた。

Research Products

• [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., Tsuji, R., Ohshima, T., Shibasaki M.
  • Journal Title: J.Am.Chem.Soc. 127 Pages: 2147-2155
• [Journal Article] Strategy for Enantio- and Diastereoselective Syntheses of All Possible Stereoisomers of 1,3-Polyol Arrays Based on a Highly Catalyst-Controlled Epoxidation of α,β-Unsaturated Morpholinyl Amides : Application to Natural Product Synthesis (2004)
  • Author(s): Tosaki, S.-y., Horiuchi, Y., Nemoto, T., Ohshima, T., Shibasaki, M.
  • Journal Title: Chem.Eur.J. 10 Pages: 1527-1544
• [Journal Article] Enantioselective Syntheses and Biological Studies of Aeruginosin 298-A and its Analogues : Application of Catalytic Asymmetric Phase-Transfer Reaction (2004)
  • Author(s): Fukuta, Y., Ohshima, T., Gnanadesikan, V., Shibuguchi T., Nemoto, T., Kisugi, T., Okino, T., Shibasaki, M.
  • Journal Title: Proc.Natl.Acad.Sci. 101 Pages: 5433-5438
• [Journal Article] Catalytic asymmetric phase-transfer reactions using tartrate-derived asymmetric two-center organocatalysts (2004)
  • Author(s): Ohshima, T., Shibuguchi, T., Fukuta, Y., Shibasaki, M.
  • Journal Title: Tetrahedron 60 Pages: 7743-7754
• [Journal Article] Direct Catalytic Asymmetric Aldol-Tishchenko Reaction (2004)
  • Author(s): Gnanadesikan, V., Horiuchi, Y., Ohshima, T., Shibasaki, M.
  • Journal Title: J.Am.Chem.Soc. 126 Pages: 7782-7783
• [Journal Article] Enantioselective total synthesis of (-)-strychnine : development of a highly practical catalytic asymmetric carbon-carbon bond formation and domino cyclization (2004)
  • Author(s): Ohshima, T., Xu, Y., Takita, R., Shibasaki, M.
  • Journal Title: Tetrahedron 60 Pages: 9569-9588
• [Journal Article] Enantioselective Total Syntheses of Several Bioactive Natural Products Based on the Development of Practical Asymmetric Catalysis (2004)
  • Author(s): Ohshima, T.
  • Journal Title: Chem.Pharm.Bull. 52 Pages: 1031-1052
  • NAID: 110003615717
• [Journal Article] Asymmetric Heck Reaction
  • Author(s): Shibasaki, M., Vogl, E.M., Ohshima, T.
  • Journal Title: Adv.Synth.Catal. (印刷中)
• [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
  • Author(s): Takita, R., Fukuta, Y., Tsuji, R., Ohshima, T., Shibasaki, M.
  • Journal Title: Org.Lett. (印刷中)
• [Journal Article] Formal Total Synthesis of (+)-Wortmannin Using Catalytic Asymmetric Intramolecular Aldol Condensation Reaction
  • Author(s): Shigehisa, H., Mizutani, T., Tosaki, S.-y., Ohshima, T., Shibasaki, M.
  • Journal Title: Tetrahedron (印刷中)
• [Book] Multimetallic Catalysts in Organic Synthesis (Group 13-Alkali Metal Heterobimetallic Asymmetric Catalysis) (2004)
  • Author(s): Ohshima, T., Shibasaki, M.
  • Total Pages: 295
  • Publisher: WILEY-VCH
• [Publications] Tosaki, S.-y., Nemoto, T., Ohshima, T., Shibasaki, M.: "Catalytic Asymmetric Synthesis of Both syn- and anti-3,5-Dihydroxy Esters : Application to 1,3-Polyol/α-Pyrone Natrural Product Synthesis"Org.Lett.. 5. 495-498 (2003)
• [Publications] Nemoto, T., Tosaki, S.-y., Ohshima, T., Shibasaki, M.: "Unique Reactivity of α,β-Unsaturated Carboxylic Acid Imidazolides : Catalytic Asymmetric synthesis of α,β-Epoxy Esters and α,β-Epoxy Carboxylic Acid Derivatives"Chirality. 15. 306-311 (2003)
• [Publications] Nemoto, T., Ohshima, T., Shibasaki, M.: "Enantioselective total syntheses of (+)-decursin and related natural compounds using catalytic asymmetric epoxidation of an enone"Tetrahedron. 59. 6889-6897 (2003)
• [Publications] Ohshima, T., Nemoto, T., Tosaki, S.-y., Kakei, H., Gnanadesikan, V., Shibasaki, M.: "Catalytic asymmetric epoxidation of α,β-unsaturated carboxylic acid imidazolides and amides by lanthanide-BINOL complexes"Tetrahedron. 59. 10485-10497 (2003)
• [Publications] Ohshima, T., Gnanadesikan, V., Shibuguchi, T., Fukuta, Y., Nemoto, T., Shibasaki, M.: "Enantioselective Syntheses of Aeruginosin 298-A and its Analogs Using Catalytic Asymmetric Phase-Transfer Reaction and Epoxidation"J.Am.Chem.Soc. 125. 11206-11207 (2003)
• [Publications] Majima, K., Takita, R., Okada, A., Ohshima, T., Shibasaki, M.: "Catalytic Asymmetric Michael Reaction of β-Keto Esters : Effects of the Linker Heteroatom in Linked-BINOL"J.Am.Chem.Soc. 125. 15837-15845 (2003)
• [Publications] Kakei, H., Nemoto, T., Ohshima, T., Shibasaki, M.: "Efficient Synthesis of Chiral α- and β-Hydroxy Amides : Application to Catalytic Asymmetric Synthesis of (R)-Fluoxetine"Angew.Chem.,Int.Ed.. 43. 317-420 (2004)
• [Publications] Tosaki, S.-y., Horiuchi, Y., Nemoto, T., Ohshima, T., Shibasaki, M.: "Strategy for Enantio- and Diastereoselective Syntheses of All Possible Stereoisomers of 1,3-Polyol Arrays Based on a Highly Catalyst-Controlled Epoxidation of α,β-Unsaturated Morpholinyl Amides : Application to Natural Product Synthesis"Chem.Eur.J.. (in press).
• [Publications] Fukuta, Y., Ohshima, T., Guanadesikan, V., Shibuguchi, T., Nemoto, T., Kisugi, T., Okino, T., Shibasaki, M.: "Enantioselective Syntheses and Biological Studies of Aeruginosin 298-A and its Analogues : Application of Catalytic Asymmetric Phase-Transfer Reaction"Proc.Natl.Acad.Sci.. (in press).
• [Publications] Matsunaga, S., Ohshima, T., Shibasaki, M.: "Linked-BINOL -an Approach towards Practical Asymmetric Multifunctional Catalysis-"Adv.Synth.Catal.. 344. 3-15 (2002)
• [Publications] Nemoto, T., Ohshima, T., Shibasaki, M.: "Catalytic Asymmetric Epoxidation of α,β-Unsaturated Carbonyl Compounds"Journal of Synthetic Organic Chemistry, Japan. 60. 94-105 (2002)
• [Publications] Sekine, A., Ohshima, T., Shibasaki, M.: "An enantioselective formal synthesis of 4-demethoxydaunomycin using the catalytic asymmetric ring opening reaction of meso-epoxide with p-anisidine"Tetrahedoron. 58. 75-82 (2002)
• [Publications] Xu, Y., Ohori, K., Ohshima, T., Shibasaki, M.: "A practical large-scale synthesis of enantiomerically pure 3-[bis(methoxycarbonyl)methyl]cyclohexanone via catalytic asymmetric michael reaction"Tetrahedoron. 58. 2585-2588 (2002)
• [Publications] Takita, R., Ohshima, T., Shibasaki, M.: "Highly enantioselective catalytic Michael reaction of α-substituted malonates using La-linked-BINOL complex in the presence of HFIP (1,1,1,3,3,3-hexafluoroisopropanol)"Tetrahedoron Lett.. 43. 4661-4665 (2002)
• [Publications] Shibasaki, M., Kanai, M., Ohshima, T., Nemoto, T.: "Development of New Asymmetric Reactions Using Rare Earths Containing Asymmetric Catalysts"RARE EARTHS. 41. 37-42 (2002)
• [Publications] Nemoto, T., Tosaki, S., Ohshima, T, Shibasaki, M.: "Unique Reactivity of α,β-Unsaturated Carboxylic Acid Imidazolides : Catalytic Asymmetric Synthesis of α,β-Epoxy Esters and α,β-Epoxy Carboxylic Acid Derivatives"Chirality. 15. 306-311 (2003)
• [Publications] Nemoto, T., Kakei, H., Gnanadesikan, V., Tosaki, S., Ohshima, T., Shibasaki, M.: "Catalytic Asymmetric Epoxidation of α,β-Unsaturated Amides : Efficient Synthesis of β-Aryl α-Hydroxy Amides Using a One Pot Tandem Catalytic Asymmetric Epoxidation-Pd-Catalyzed Epoxide Opening Process"J.Am.Chem.Soc.. 124. 14544-14545 (2002)
• [Publications] Ohshima, T., Xu, Y., Takita, R., Shimizu, S., Zhong, D., Shibasaki, M.: "Enantioselective Total Synthesis of (-)-Strychnine Using the Catalytic Asymmetric Michael Reaction and Tandem Cyclization"J.Am.Chem.Soc.. 124. 14546-14547 (2002)
• [Publications] Shibuguchi, T., Fukuta, Y., Akachi, Y., Sekine, A., Ohshima T., Shibasaki, M.: "Development of new asymmetric two-center catalysts in phase-transfer reactions"Tetrahedoron Lett.. 43. 9539-9543 (2002)
• [Publications] Tosaki, S., Nemoto, T., Ohshima, T., Shibasaki, M.: "Catalytic Asymmetric Synthesis of Both syn-and anti-3,5-Dihydroxy Esters : Application to 1,3-Polyol/α-Pyrone Natural Product Synthesis"Org.Lett.. 5. 495-498 (2003)