多段階ワンポットプロセスの開発と天然物の触媒的不斉合成への応用

1998 Fiscal Year Annual Research Report

• Project/Area Number: 10125207
• Research Institution: The University of Tokyo
• Principal Investigator: 柴崎 正勝 東京大学, 大学院・薬学系研究科, 教授 (30112767)
• Co-Investigator(Kenkyū-buntansha): 金井 求 東京大学, 大学院・薬学系研究科, 助手 (20243264) ; 飯田 剛彦 東京大学, 大学院・薬学系研究科, 助手 (40292958)
• Keywords: 触媒的不斉ヘック反応 / PI3キナーゼ阻害剤 / ワートマンニン / Tol-BINAP-パラジウム錯体 / 速度論的分割 / 相対配置 / 鈴木クロスカップリング / ワンポット触媒的不斉プロセス

Research Abstract

触媒的不斉ヘック反応を鍵工程とする、PI3キナーゼ阻害剤ワートマンニンの不斉全合成を目的として研究を行った。その結果20mol%のTol-BINAP-パラジウム錯体の制御によりラセミ体原料の速度論的分割が高エナンチオ選択的に進行し、鍵中間体であるヘック反応成績体力96%eeで得られることを見出した。すなわち、ラセミ体原料を20mol%の酢酸パラジウム、40mol%のTol-BINAP、250mol%の炭酸カリウムの存在下、トルエン溶媒中100度で反応させることにより、分子内ヘック反応の進行した3環性鍵中間体が収率20%、96%ee、ジアステレオ選択性11:1で得られた。本反応は触媒的不斉ヘック反応を速度論的分割に応用したはじめての例であり、さらに相対配置までを高度に選択している点で評価される。今後、鈴木クロスカップリング反応と組み合わせて鈴木クロスカップリング-ヘックワンポット触媒的不斉プロセスの開発により、より高効率な合成法を確立すると同時に、ワートマンニンの全合成に向けて研究を続けていく予定である。

Research Products

• [Publications] T.Arai,H.Sasai,K.Yamaguchi and M.Shibasaki: "Regioselective Catalytic Asymmetric Reation of Horner-Wadsworth-Emmons Reagents with Enones:The Odyssey of Chiral Aluminum Catalysts" J.Am.Chem.Soc.120. 441-442 (1998)
• [Publications] M.Sodeoka,M.A.Arai,K.Adachi,K.Uotsu and M.Shibasaki: "Rational Design,Synthesis,and Evaluation of a New Type of PKC inhibitor" J.Am.Chem.Soc.120. 457-458 (1998)
• [Publications] S.Y.Cho and M.Shibasaki: "Synthesis and Evaluation of a New Chiral Ligand:2-diphenylarsino-2´-diphenylphosphino-1,1´-binaphthyl(BINAPAs)" Tetrahedron Lett.39. 1773-1776 (1998)
• [Publications] A.Kojima,T.Takemoto,M.Sodeoka and M.Shibasaki: "Catalytic Asymmetric Sythesis of Halenaquinone and Halenaquinol" Synthesis. 581-589 (1998)
• [Publications] H.Groger,Y.Saida,H.Sasai,K.Yamaguchi,J.Martens and M.Shibasaki: "A New and Highly Efficient Asymmetric Route to Cyclic α-Amino Phosphonates:The First Catalytic Enantioselective Hydrophosphonylation of Cyclic Imines Catalyzed by Chiral Heterobimetallic Lanthanoid" J.Am.Chem.Soc.120. 3089-3103 (1998)
• [Publications] E.Emori,T.Arai,H.Sasai and M.Shibasaki: "A Catalytic Michael Addition of Thiols to α,β-Unsaturated Carbonyl Compounds:Asymmetric Protonations" J.Am.Chem.Soc.120. 4043-4044 (1998)
• [Publications] M.Shibasaki,T.Iida,Y.M.A.Yamada: "Development of Multifunctional Asymmetric Catalysts and Their Application to Practical Organic Synthesis" 有機合成化学協会誌. 56. 344-356 (1998)
• [Publications] T.Morita,T.Arai,H.Sasai and M.Shibasaki: "Utilization of heterobimetallic complexes as Lewis acids" Tetrahedron:Asymmetry. 9. 1445-1450 (1998)
• [Publications] M.Sodeoka and M.Shibasaki: "Asymmetric synthesis using palladium catalysts" Pure & Appl.Chem.70. 411-414 (1998)
• [Publications] K.Yamada,Y.Arai,H.Sasai and M.Shibasaki: "A Catalytic Asymmetric Synthesis of II-Deoxy-PGF_<1α> Using ALB,a Heterobimetallic Multifunctional Asymmetric Complex" J.Org.Chem.63. 3666-3672 (1998)
• [Publications] Y.M.A.Yamada and M.Shibasaki: "Direct Catalytic Asymmetric Aldol Reactions Promoted by a Novel Barium Complex" Tetrahedron Letters.39. 5561-5564 (1998)
• [Publications] M.Shibasaki,H.Sasai,T.Arai and T.Iida: "Heterobimetallic asymmetric catalysts Developments and applications" Pure & Appl.Chem.70. 1027-1034 (1998)
• [Publications] M.Shibasaki and K.Uotsu: "PKC activations and inhibitors" IGAKUSHOIN. 49. 290-295 (1998)
• [Publications] K.Uotsu,M.Sodeoka and M.Shibasaki: "Photoaffinity Labeling of PKC lsozymes by Phorbol Ester Derivatives" Bioorg.& Med.Chem.6. 1117-1126 (1998)
• [Publications] H.Groes,E.M.Vogl and M.Shibasaki: "New Catalytic Concepts for the Asymmetric Aldol Reation" Chem.Eur.J.4. 1137-1141 (1998)
• [Publications] T.Iida,N.Yamamoto,H.-G.Woo and M.Shibasaki: "Enantioselective Ring Opening of Epoxides with 4-Methoxyphenol Catalyzed by Gallium Heterobimetallic Complexes:An Efficient Method for the Synthesis of Optically Active 1,2-Diol Monoethers" Angew.Chem.Int.Ed.Engl.37. 2223-2226 (1998)
• [Publications] M.Shibasaki,H.Sasai T.Arai and T.Iida: "Heterobimetallic asymmetric catalysts Developments and applications" Pure & Appl.Chem.70. 1027-1034 (1998)
• [Publications] E.M.Vogl,S.Matsunaga,M.Kanai,T.Iida and M.Shibasaki: "Linking BINOL:C_2-Symmetric Ligands for Investigations on Asymmetric Catalysis" Tetrahedron Letters. 39. 7917-7920 (1998)
• [Publications] F.Miyazaki,K.Uotsu and M.Shibasaki: "Silver Salt Effects on an Asymmetric Heck Reation.Catalytic Asymmetric Total Synthesis of (+)-Xestoquinone." Tetrahedron. 54. 13073-13078 (1998)
• [Publications] S.Shimizu,K.Ohori,T.Arai,H.Sasai and M.Shibasaki: "A Catalytic Asymmetric Synthesis of Tubifolidine" J.Org.Chem.63. 7547-7551 (1998)
• [Publications] K.Funabashi,Y.Saida,M.Kanai.T.Arai,H.Sasai and M.Shibasaki: "Catalytic Asymmetric Michael Adition of Nitromethane to Enones Controlled by (R)-LPB" Tetrahedron Letters. 39. 7557-7558 (1998)
• [Publications] S.Watanabe,Y.Kobayashi,T.Arai,H.Sasai,M.Bougauchi and M.Shibasaki: "Water vs.Desiccant.Improvement of Yb-BINOL Complex Catalyzed Enantioselective Epoxidation of Enones" Tetrahedron Letters. 39. 7353-7356 (1998)
• [Publications] M.Shibasaki,A.Kojima and S.Shimizu: "Catalytic Asymmetric Synthesis of Natural Products with Heterocyclic Rings" J.Heterocyclic Chem.35. 1057-1064 (1998)
• [Publications] S.Watanabe,T.Arai,H.Sasai,M.Bougauchi and M.Shibasaki: "The First Catalytic Enatioselective Synthesis of cis-Epoxyketones from cis-Enones" J.Org.Chem.63. 8090-8091 (1998)
• [Publications] S,Y.Cho and M.Shibasaki: "The symmetric of cyclopentane derivatives by palladium-catalyzed coupling of prochiral alkylboron" Tetrahedron:Asymmetry. 9. 3751-3754 (1998)
• [Publications] S.Yamasaki,T.Iida and M.Shibasaki: "Direct Catalytic Asymmetric Mannich-type Reaction of Unmodified Ketones Utilizing the Cooperation of an AlLibis(binaphthoxide) Complex and La(OTY), nH_2O" Tetrahedron Lett.40. 307-310 (1999)
• [Publications] S.Honzawa,T.Mizutani and M.Shibasaki: "Synthetic Studies on (+)-Wortmannin An Asymmetric Construction of an Allylic Quaternary Carbon Center by a Heck Reaction" Tetrahedron Lett.40. 311-314 (1999)