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Highly selective fine organic synthesis

Research Project

Project/Area Number 02403026
Research Category

Grant-in-Aid for General Scientific Research (A)

Allocation TypeSingle-year Grants
Research Field Chemical pharmacy
Research InstitutionHokkaido University

Principal Investigator

YONEMITSU Osamu  Hokkaido University, Faculty of Pharmaceutical Sciences, Professor, 薬学部, 教授 (60001038)

Co-Investigator(Kenkyū-buntansha) NAKAJIMA Noriyuki  Hokkaido University, Faculty of Pharmaceutical Sciences, Instructor, 薬学部, 助手 (40188959)
HORITA Kiyoshi  Hokkaido University, Faculty of Pharmaceutical Sciences, Instructor, 薬学部, 助手 (50181540)
NISHIDA Atsushi  Hokkaido University, Faculty of Pharmaceutical Sciences, Instructor, 薬学部, 助手 (80130029)
HAMADA Tatsuo  Hokkaido University, Faculty of Pharmaceutical Sciences, Associate Professor, 薬学部, 助教授 (40001979)
Project Period (FY) 1990 – 1993
Project Status Completed (Fiscal Year 1993)
Budget Amount *help
¥32,100,000 (Direct Cost: ¥32,100,000)
Fiscal Year 1993: ¥2,000,000 (Direct Cost: ¥2,000,000)
Fiscal Year 1992: ¥2,000,000 (Direct Cost: ¥2,000,000)
Fiscal Year 1991: ¥6,000,000 (Direct Cost: ¥6,000,000)
Fiscal Year 1990: ¥22,100,000 (Direct Cost: ¥22,100,000)
KeywordsMacrolide antibiotic / Polyether antibiotic / Polyether macrolide / Asymmetric radical cyclization / Hetero Diels-Alder reaction / Sereoselective reaction / Computer chemistry / Conformational control / アグリコン / 立体制御 / NMR / 保護基 / ポリエ-テル抗生物質 / マクロリドポリエ-テル / 分子力場計算
Research Abstract

The object of this research was to contribute to the progress of modern fine organic synthetic chemistry through the development of a new methodology for selective and efficient syntheses of very complex molecules such as macrolide and polyether antilbiotics and marine polyether-macrolides. During the past four years research the following five results were mainly obtained.
1. Synthsis of macrolides : Erythromolide A, the most important aglycon, was synthesized via an extremely efficient macrolactionization with the aid of MM2-CONFLEX3 calculation and NMR analysis of a seco-acid derivative, Carbonolide A, leuconolides, and maridonolides were also synthesized completely stereoselectively from carbonolide B through conformational control of 16-membered macro-rings.
2. Synthesis of polyethers : Highly stereoselective synthesis of complex isolasalocid A, lasalocid A, salinomycin, and lysocellin by a common methodology was completed.
3. Synthesis of polyether-macrolides : Stereoselective synthesis of four fragments of halichondrin B was completed, and coupling among the fragments is in progress.
4. Asymmetric radical cyclization : A new method for the synthesis of optically active five and six membered rings was developed via asymmtric radical cyclization between an acetylene and an alpha, beta-unsaturated ester in the presence of a Lewis acid.
5. Hetero Diels-Alder reaction : One-step synthesis of optically active dihydropyridine derivatives was developed via a hetero Diels-Alder reaction between tosylimines and diene derivatives. This method was successfully applied for the synthesis of a polyamine alkaloid, cannabisativine.

Report

(5 results)
  • 1993 Annual Research Report   Final Research Report Summary
  • 1992 Annual Research Report
  • 1991 Annual Research Report
  • 1990 Annual Research Report
  • Research Products

    (36 results)

All Other

All Publications (36 results)

  • [Publications] Horita,K.: "Stereoselective Total Synthesis of Polyether Ionophore Antibiotics.Isolasalocid A and Lasalocid A.Part 2.The Total Synthesis via Stereoselective Construction of the B-Rings by Chelation-Controlled Cyclization under Thermodynamic Conditions." Tetrahedron. 49. 5997-6018 (1993)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] Horita,K.: "Stereoselective Synthesis of Optically Active 3,5-Dihydroxy-4-ethyl-2-methylpentyl Derivatives.A Basic Building Block with Three Contiguous Chiral Centers of Polyether Antibiotics." Chem.Pharm.Bull.41. 2044-2046 (1993)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] Nishida,A.: "New Methods for the Preparation of Optically Active Carbocycles:Asymmetric Acetalization and Lewis Acid Promoted Diastereoselective Radical Cyclization." J.Org.Chem.58. 5870-5872 (1993)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] Horita,K.: "Synthetic Studies of Halichondrin B,a Antitumor Polyether Macrolide Isolated from a Marine Sponge.3.Synthesis of the C27-C36 Subunit via Completely Stereoselective C-Glycosylation to the F Ring." Synlett. 43-45 (1994)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] Horita,K.: "Synthetic Studies of Halichondrin B,a Antitumor Polyether Macrolide Isolated from a Marine Sponge.4.Synthesis of the C37-C54 Subunit via Stereoselective Construction of Three Consecutive J,K,and L Rings." Synlett. 46-48 (1994)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] Horita,K.: "Large Laboratory Scale Synthesis of (2S,3S)-2-(4-Methoxybenzyloxy)-3,4-pentylidene-dioxybutan-1-ol,a Versatile Chiral Building Block in Natural Product Synthesis." Chem.Pharm.Bull.42. 683-685 (1994)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] Horita, K. ; Noda, I. ; Tanaka, K. ; Oikawa, Y. ; Yonemitsu, O.: "Stereoselective Total Synthesis of Polyether Ionophore Antibiotics, Isolasalocid A and Lasalocid A.Part 2. The Total Synthesis via Stereoselective Construction of the B-Rings by Chelation-Controlled Cyclization under Thermodynamic Conditions." Tetrahedron. 49. 5997-6018 (1993)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] Horita, K. ; Tanaka, K. ; Yonemitsu, O.: "Stereoselective Synthesis of Optically Active 3,5-Dihydroxy-4-ethyl-2-methylpentyl Derivatives. A Basic Building Block with Three Contiguous Chiral Centers of Polyether Antibiotics." Chem.Pharm.Bull.41. 2044-2046 (1993)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] Nishida, A. ; Nishida, M. ; Yonemitsu, O.: "New Methods for the Preparation of Optically Active Carbocycles : Asymmetri Acetalization and Lewis Acid Promoted Diastereoselective Radical Cyclization." J.Org.Chem.58. 5870-5872 (1993)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] Horita, K. ; Hachiya, S. ; Nagasawa, M. ; Hikota, M. ; Yonemitsu, O.: "Synthetic Studies of Halichondrin B, an Antitumor Polyether Macrolide Isolated from a Marine Sponge. 1. Stereoselective Synthesis of the C1-C13 Fragment via Construction of the B and A Rings by Kinetically and Theremodynamically Controlled Intramolecular Michael Reactions." Synlett. 38-40 (1994)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] Horita, K. ; Nagasawa, M. ; Hachiya, S. ; Yonemitsu, O.: "Synthetic Studies of Halichondrin B, an Antitumor Polyether Macrolide Isolated from a Marine Sponge. 2. Efficient Synthesis of C16-C26 Fragments via Construction of the D Ring by a Highlty Stereocontrolled Iodoetherification." Synlett. 40-43 (1994)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] Horita, K. ; Sakurai, Y. ; Nagasawa, M. ; Hachiya, S. ; Yonemitsu, O.: "Synthetic Studies of Halichondrin B, an Antitumor Polyether Macrolide Isolated from a Marine Sponge. 3. Synthesis of the C27-C36 Subunit via Completely Stereoselective C-Glycosylation to the F Ring." Synlett. 43-45 (1994)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] Horita,K.: "Stereoselective Total Synthesis of Polyther Ionophore Antibiotics,Isolasalocid A and Lasalocid A.Part 2.The Total Synthesis via Stereoselective Construction of the B-Rings by Chelation-Controlled Cyclization under Thermodynamic Conditions." Tetrahedron. 49. 5997-6018 (1993)

    • Related Report
      1993 Annual Research Report
  • [Publications] Horita,K.: "Stereoselective Synthesis of Optically Active 3,5-Dihydroxy-4-ethyl-2-methylpentyl Derivatives.A Basic Building Block with Three Contiguous Chiral Centers of Polyether Antibiotics." Chem.Pharm.Bull.41. 2044-2046 (1993)

    • Related Report
      1993 Annual Research Report
  • [Publications] Nishida,A.: "New Methods for the Preparation of Optically Active Carbocycles: Asymmetric Acetalization and Lewis Acid Promoted Diastereoselective Radical Cyclization." J.Org.Chem.58. 5870-5872 (1993)

    • Related Report
      1993 Annual Research Report
  • [Publications] Horita,K.: "Synthetic Studies of Halichondrin B,a Antiumor Polyether Macrolide Isolated from a Marine Sponge.3.Synthesis of the C27-C36 Subunit via Completely Stereoselective C-Glycosylation to the F Ring." Synlett. 43-45 (1994)

    • Related Report
      1993 Annual Research Report
  • [Publications] Horita,K.: "Synthetic Studies of Halichondrin B,a Antitumor Polyether Macrolide Isolated from a Marine Sponge.4.Synthesis of the C37-C54 Subunit via Stereoselective Construction of Three Consecutive J,K,and L Rings." Synlett. 46-48 (1994)

    • Related Report
      1993 Annual Research Report
  • [Publications] Horita,K.: "Large Laboratory Scale Synthesis of (2S,3S)-2-(4-Methoxybenzyloxy)-3,4-pentylidene-dioxybutan-1-ol,a Versatile Chiral Building Block in Natural Product Syntesis." Chem.Pharm.Bull.42. 683-685 (1994)

    • Related Report
      1993 Annual Research Report
  • [Publications] K.Hirao: "New Route to 2-Substituted Indoles by Phyolysis of N-Acetylphenylhydroxylamines." Tetrahedron Lett.33. 1459-1462 (1992)

    • Related Report
      1992 Annual Research Report
  • [Publications] T.Matushima: "Conformational Analysis of the 16-Membered Epoxyenone and Complete Stereoseletion in the Macrolide Synthesis." Tetrahedron. 48. 4525-4532 (1992)

    • Related Report
      1992 Annual Research Report
  • [Publications] Y.Sakurai: "Synthesis of Erythronolide a via Direct Macrolactonization of a Conformationally Controlled Seco-acid with the Yamaguchi Reagent." Chem.Pharm.Bull.40. 2540-2542 (1992)

    • Related Report
      1992 Annual Research Report
  • [Publications] K.Horita: "Total Synthesis of the Polyether Antibiotic Lysocellin.1.Stereocontrolled Synthesis of Fragments." Tetrahedron Lett.33. 5537-5540 (1992)

    • Related Report
      1992 Annual Research Report
  • [Publications] K.Horita: "Total Synthesis of the Poltether Antibiotic Lysocellin.2.Stereocontrolled Synthesis." Tetrahedron Lett.33. 5541-5544 (1992)

    • Related Report
      1992 Annual Research Report
  • [Publications] K.Hirao: "Synthesis of 2,9-Dimethyl-p-[3^2.5^6]octahedrane." J.Chem.Res.(M). 2601-2609 (1992)

    • Related Report
      1992 Annual Research Report
  • [Publications] Nakajima,N.: "Facile Total Synthesis of Carbonolides by WittigーHorner MacroーCyclization and Stereoselective Epoxidation." Chem.Pharm.Bull.39. 64-74 (1991)

    • Related Report
      1991 Annual Research Report
  • [Publications] Hamada,T.: "A Chiral Synthesis of(-)ーCannabisativine:An Application of the Highly Diastereoーselective Hetero DielsーAlder Reaction." Tetrahedron Lett.32. 1649-1652 (1991)

    • Related Report
      1991 Annual Research Report
  • [Publications] Matsushima,T.: "Two Distinct Conformational Isomers of the 16ーMembered Epoxyenone,the Key Synthetic Intermediate of Maridono^^´lides." Tetrahedron Lett.32. 5133-5136 (1991)

    • Related Report
      1991 Annual Research Report
  • [Publications] Nakajima,N.: "Stereoselective Total Synthesis of 16ーMembered Macrolide Aglycons,Leuconolides and Maridonolides.Macrocyclic Stereocontorol Based on the Conformational Analysis of 16ーMembered Macrolide Ring." Chem.Pharm.Bull.39. 2819-2829 (1991)

    • Related Report
      1991 Annual Research Report
  • [Publications] Hirao,K.: "New Route to 2ーSubstituted IndoIes by Pyrolysis of NーAcylacetylーphenylhydroxylamines." Tetrahedron Lett.(1992)

    • Related Report
      1991 Annual Research Report
  • [Publications] Matsushima,T.: "Conformational Analysis of the 16ーMembered Epoxyenone and Complete Stereoselection in the Reduction of its C9 Carbonyl Group,the Key Reaction in the Synthesis of Macrolides." Tetrahedron,. (1992)

    • Related Report
      1991 Annual Research Report
  • [Publications] Nishida,A.;Takahashi,H.;Takeda,H.;Takada,N.;Yonemitsu,O.: "Sequential Radical Cyclization,Alkoxy Radical Fragmentation,and Recyclization Processes:A Novel Method for the Synthesis of Fused Cycloheptanones and Cyclooctenones from Cyclohexanones." J.Am.Chem.Soc.112. 902-904 (1990)

    • Related Report
      1990 Annual Research Report
  • [Publications] Nakajima,N.;Uoto,K.;Matsushima,T.;Yonemitsu,O.;Goto,H.;Osawa,E.: "Synthesis of 16ーMembered Macrolide Aglycones,Carbonolide A,Leuconolides and Maridonolides,via Carbonolide B Type Compounds by Virtue of Completely Stereoselective Epoxidation and Reduction Based on the Conformational Control of Macrolide Rings with Protecting Groups." J.Org.Chem.55. 1129-1132 (1990)

    • Related Report
      1990 Annual Research Report
  • [Publications] Hikota,M.;Tone,H.;Horita,K.;Yonemitsu,O.: "Stereoselective Synthesis of Erythronolide A by Extremely Efficient Lactonization Based on Conformational Adjustment and High Activation of SecoーAcid." Tetrahedron. 46. 4613-4628 (1990)

    • Related Report
      1990 Annual Research Report
  • [Publications] Hikota,M.;Sakurai,Y.;Horita,K.;Yonemitsu,O.: "Synthesis of Erythronolide A via a Very Efficient Macrolactonization under Usual Acylation Conditions with the Yamaguchi Reagent." Tetrahedron Lett.31. 6367-6370 (1990)

    • Related Report
      1990 Annual Research Report
  • [Publications] Nishida,A.;Hamada,T.;Yonemitsu,O.: "Extremely Mild and Selective Method for Hydrolysis of Tosyl Esters by Photoーsensitized Single Electron Transfer Reactions." Chem.Pharm.Bull.38. 2977-2980 (1990)

    • Related Report
      1990 Annual Research Report
  • [Publications] Nishida,A.;Nishida,M.;Yonemitsu,O.: "Generation and Intramolecular Cyclization of Free Radicals at the Carbon between Two Heteroatoms under NonーReductive Conditions." Tetrahedron Lett.31. 7035-7038 (1990)

    • Related Report
      1990 Annual Research Report

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Published: 1990-04-01   Modified: 2016-04-21  

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