創薬の基礎となる高選択的精密有機合成

• 研究課題/領域番号: 02403026
• 研究種目: 一般研究(A)
• 配分区分: 補助金
• 研究分野: 化学系薬学
• 研究機関: 北海道大学
• 研究代表者: 米光 宰 北海道大学, 薬学部, 教授 (60001038)
• 研究分担者: 中島 範行 北海道大学, 薬学部, 助手 (40188959) ; 堀田 清 北海道大学, 薬学部, 助手 (50181540) ; 西田 篤司 北海道大学, 薬学部, 助手 (80130029) ; 浜田 辰夫 北海道大学, 薬学部, 助教授 (40001979)
• 研究期間 (年度): 1990 – 1993
• 研究課題ステータス: 完了 (1993年度)
• 配分額: 32,100千円 (直接経費: 32,100千円); 1993年度: 2,000千円 (直接経費: 2,000千円); 1992年度: 2,000千円 (直接経費: 2,000千円); 1991年度: 6,000千円 (直接経費: 6,000千円); 1990年度: 22,100千円 (直接経費: 22,100千円)
• キーワード: マクロリド抗生物質 / ポリエーテル抗生物質 / ポリエーテルマクロリド / 不斉ラジカル環化反応 / ヘテロジールスアルダー反応 / 立体選択的反応 / 計算化学 / コンホメーション制御 / 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

研究概要

本研究は,極めて複雑な構造をもつマクロリド,ポリエーテル抗生物質などの選択的効率的合成のための方法論を開発し,現代精密有機合成化学の進歩に寄与し,さらに次代の創薬への合成化学的基盤の向上を目指したものである。4年間の研究により,以下に概要を示す5研究項目で成果を上げることができ,当初の目的に達しえたと考えられる。
1.マクロリド合成:NMRの精密測定とMM2-CONFLEX3計算によるセコ酸のコンホメーション解析とDMAPによる活性化による超効率ラクトン化法を開発し,エリスロノリドAの合成を行った。また16員環ラクトンのコンホメーション解析と制御によるカルボノリド,ロイコノリド,マリドノリドなどの立体選択的合成を完成した。
2.ポリエーテル合成:イソラサロシド,ラサロシド,サリノマイシン,リソセリンなどの立体選択的合成法を確立した。
3.ポリエーテルマクロリド合成:海洋産のハリコンドリンBの4つのフラグメントをそれぞれ立体選択的に合成し,フラグメント間の縮合を検討中であり,近い将来に合成が完了する。
4.不斉ラジカル環化反応:ルイス酸存在下,アセチレンとα,β-不飽和エステルとの間の不斉ラジカル環化反応を開発し,これにより光学活性5員環,6員環化合物の合成を行った。不斉ラジカル反応は新しい研究領域といえる。
5.ヘテロジールスアルダー反応:トシルイミンとジエンの光学活性誘導体間のジールスアルダー反応により不斉のジヒドロピリジン誘導体を1工程で合成する方法を開発し,ポリアミンアルカロイドのカンナビサチビンの全合成を行った。

研究成果

• [文献書誌] 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)
  • 説明: 「研究成果報告書概要(和文)」より
• [文献書誌] 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)
  • 説明: 「研究成果報告書概要(和文)」より
• [文献書誌] 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)
  • 説明: 「研究成果報告書概要(和文)」より
• [文献書誌] 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)
  • 説明: 「研究成果報告書概要(和文)」より
• [文献書誌] 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)
  • 説明: 「研究成果報告書概要(和文)」より
• [文献書誌] 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)
  • 説明: 「研究成果報告書概要(和文)」より
• [文献書誌] 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)
  • 説明: 「研究成果報告書概要(欧文)」より
• [文献書誌] 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)
  • 説明: 「研究成果報告書概要(欧文)」より
• [文献書誌] 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)
  • 説明: 「研究成果報告書概要(欧文)」より
• [文献書誌] 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)
  • 説明: 「研究成果報告書概要(欧文)」より
• [文献書誌] 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)
  • 説明: 「研究成果報告書概要(欧文)」より
• [文献書誌] 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)
  • 説明: 「研究成果報告書概要(欧文)」より
• [文献書誌] 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)
• [文献書誌] 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)
• [文献書誌] 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)
• [文献書誌] 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)
• [文献書誌] 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)
• [文献書誌] 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)
• [文献書誌] K.Hirao: "New Route to 2-Substituted Indoles by Phyolysis of N-Acetylphenylhydroxylamines." Tetrahedron Lett.33. 1459-1462 (1992)
• [文献書誌] T.Matushima: "Conformational Analysis of the 16-Membered Epoxyenone and Complete Stereoseletion in the Macrolide Synthesis." Tetrahedron. 48. 4525-4532 (1992)
• [文献書誌] 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)
• [文献書誌] K.Horita: "Total Synthesis of the Polyether Antibiotic Lysocellin.1.Stereocontrolled Synthesis of Fragments." Tetrahedron Lett.33. 5537-5540 (1992)
• [文献書誌] K.Horita: "Total Synthesis of the Poltether Antibiotic Lysocellin.2.Stereocontrolled Synthesis." Tetrahedron Lett.33. 5541-5544 (1992)
• [文献書誌] K.Hirao: "Synthesis of 2,9-Dimethyl-p-[3^2.5^6]octahedrane." J.Chem.Res.(M). 2601-2609 (1992)
• [文献書誌] Nakajima,N.: "Facile Total Synthesis of Carbonolides by WittigーHorner MacroーCyclization and Stereoselective Epoxidation." Chem.Pharm.Bull.39. 64-74 (1991)
• [文献書誌] 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)
• [文献書誌] 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)
• [文献書誌] 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)
• [文献書誌] Hirao,K.: "New Route to 2ーSubstituted IndoIes by Pyrolysis of NーAcylacetylーphenylhydroxylamines." Tetrahedron Lett.(1992)
• [文献書誌] 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)
• [文献書誌] 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)
• [文献書誌] 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)
• [文献書誌] 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)
• [文献書誌] 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)
• [文献書誌] 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)
• [文献書誌] 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)