Highly selective fine organic synthesis

• Project/Area Number: 02403026
• Research Category: Grant-in-Aid for General Scientific Research (A)
• Allocation Type: Single-year Grants
• Research Field: Chemical pharmacy
• Research Institution: Hokkaido 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: ¥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)
• Keywords: Macrolide 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.

Research Products

• [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
• [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
• [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
• [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
• [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
• [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
• [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
• [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
• [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
• [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
• [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
• [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
• [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)
• [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)
• [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)
• [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)
• [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)
• [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)
• [Publications] K.Hirao: "New Route to 2-Substituted Indoles by Phyolysis of N-Acetylphenylhydroxylamines." Tetrahedron Lett.33. 1459-1462 (1992)
• [Publications] T.Matushima: "Conformational Analysis of the 16-Membered Epoxyenone and Complete Stereoseletion in the Macrolide Synthesis." Tetrahedron. 48. 4525-4532 (1992)
• [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)
• [Publications] K.Horita: "Total Synthesis of the Polyether Antibiotic Lysocellin.1.Stereocontrolled Synthesis of Fragments." Tetrahedron Lett.33. 5537-5540 (1992)
• [Publications] K.Horita: "Total Synthesis of the Poltether Antibiotic Lysocellin.2.Stereocontrolled Synthesis." Tetrahedron Lett.33. 5541-5544 (1992)
• [Publications] K.Hirao: "Synthesis of 2,9-Dimethyl-p-[3^2.5^6]octahedrane." J.Chem.Res.(M). 2601-2609 (1992)
• [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)
• [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)
• [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)
• [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)
• [Publications] Hirao,K.: "New Route to 2ーSubstituted IndoIes by Pyrolysis of NーAcylacetylーphenylhydroxylamines." Tetrahedron Lett.(1992)
• [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)
• [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)
• [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)
• [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)
• [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)
• [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)
• [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)