最強の抗腫瘍性物質デイスコダーモライドの大量供給を可能とする不斉全合成

• 研究課題/領域番号: 12554022
• 研究種目: 基盤研究(B)
• 配分区分: 補助金
• 応募区分: 展開研究
• 研究分野: 有機化学
• 研究機関: 九州大学 (2002-2003); 高知大学 (2000-2001)
• 研究代表者: 清岡 俊一 九州大学, 先導物質化学研究所, 教授 (00036584)
• 研究分担者: 後藤 文孝 大塚製薬, 有機化学研究所, 研究員 ; 藤山 亮治 高知大学, 理学部, 助教授 (50145108)
• 研究期間 (年度): 2000 – 2003
• 研究課題ステータス: 完了 (2003年度)
• 配分額: 13,300千円 (直接経費: 13,300千円); 2003年度: 2,000千円 (直接経費: 2,000千円); 2002年度: 3,100千円 (直接経費: 3,100千円); 2001年度: 3,800千円 (直接経費: 3,800千円); 2000年度: 4,400千円 (直接経費: 4,400千円)
• キーワード: 不斉アルドール反応 / ディスコダーモライド / 抗腫瘍性 / ラジカル脱ブロム化 / 鎖式立体制御 / プロピオネートアルドール / ポリケチド / キラルボラン / シン-,アンチ-プロピオネート / デイスコダーモライド / プロピオネート アルドール

研究概要

エナンチオならびにジアステレオ高選択的向山アルドール反応と続く高ジアステレオ選択的ラジカル脱ブロム化反応を併用するポリプロピオネート鎖の立体選択的構築する一般的手法が確立された。ポリプロピオネート鎖を含む多様な天然物の合成が可能となった。「Diastereoselective radical debromination approach toward divergent synthesis of syn- and anti-propionate units, coupled with enantioselective and/or diastereoselective Lewis acid-promoted aldol reaction, Tetrahedron : Asymmetry, 14, 2897-2910 (2003)」この手法を用いて、(+)-Discodermolideの大量供給可能な全合成ルートが確立し、天然物とは違った立体化学を持つ骨格合成も検討され、先行するスミスやパターソンらの合成ルートとは違ったユニークな形式全合成が完成した。各段階での選択性はいずれも高く他の系への応用も広く可能である。「Regulated-stereoselective construction of thirteen stereogenic centers necessary for the frame of (+)-discodermolide, based on iterative Lewis acid-promoted aldol reactions, J.Org.Chem.,68,7967-7978 (2003)」

研究成果

• [文献書誌] S.-i.Kiyooka et al.: "Regulated-stereoselective construction of thirteen stereogenic centers necessary for----"J.Org.Chem.. 68. 7967-7978 (2003)
• [文献書誌] S.-i.Kiyooka: "Diastereoselective radical debromination approach toward divergent synthesis of----"Tetrahedron : Asymmetry. 14. 2897-2910 (2003)
• [文献書誌] S.-i.Kiyooka: "Diastereoselective radical debromination approach toward divergent synthesis of syn- and anti-propionate units, coupled with enantioselective and/or diastereoselective Lewis acid-promoted aldol reactions"Tetrahedron : Asymmetry. 14. 2897-2910 (2003)
  • 説明: 「研究成果報告書概要(和文)」より
• [文献書誌] S.-i.Kiyooka: "Regulated-stereoselective construction of thirteen stereogenic centers necessary for the frame of (+)-discodermolide, based on iterative Lewis acid-promoted aldol reactions"J.Org.Chem.. 68. 7967-7978 (2003)
  • 説明: 「研究成果報告書概要(和文)」より
• [文献書誌] K.A.Shahid: "A straightforward, highly stereoselective construction of eight stereogenic centers in (+)-discodermolide C1-C13 segment, based on a strategy of iterative aldol reactions"Tetrahedron Lett.. 43. 6377-6381 (2002)
  • 説明: 「研究成果報告書概要(和文)」より
• [文献書誌] K.A.Shahid: "A short synthesis of the C15-C21 segment of (+)-discodermolide, based on an asymmetric approach from achiral 2-methyl-1,3-propanediol to versatile enantiopure stereotriads"Tetrahedron Lett.. 43. 6373-6376 (2002)
  • 説明: 「研究成果報告書概要(和文)」より
• [文献書誌] S.-i.Kiyooka: "A straightforward strategy toward the construction of polypropionate frameworks, based on a sequence of diastereoselective Lewis acid-mediated aldol reaction and diastereoselective radical debromination reaction"Tetrahedron Lett.. 43. 5377-5380 (2002)
  • 説明: 「研究成果報告書概要(和文)」より
• [文献書誌] S.-i.Kiyooka: "Diphenylboron perchlorate as an efficient for self- and cross-condensation reactions of aldehydes having α-active hydrogens"Tetrahedron Lett. 44. 927-930 (2003)
  • 説明: 「研究成果報告書概要(和文)」より
• [文献書誌] S.-i.Kiyooka: "Versatile, high 2,4-syn dialkyl diastereoselection in the radical debromination of α-bromo-α-methyl-δ-valerolactones with tri-butyltin hydride and a catalytic amount of triethylborane"Tetrahedron Lett. 42. 7299-7301 (2001)
  • 説明: 「研究成果報告書概要(和文)」より
• [文献書誌] S.-i.Kiyooka: "Is diphenylboronium perchlorate in nitromethane ionic?"Tetrahedron Lett. 42. 4151-4153 (2001)
  • 説明: 「研究成果報告書概要(和文)」より
• [文献書誌] S.-i.Kiyooka: "Superior substrate control on diastereoselection in boric Lewis acid-promoted aldol reactions. Asymmetric synthesis of a 3,4-syn homologous series of ethyl 3,5-dihydroxy-2,4-dimethyl-5-phenylpentanoates"Tetrahedron : Asymmetry. 12. 2343-2349 (2001)
  • 説明: 「研究成果報告書概要(和文)」より
• [文献書誌] S.-i.Kiyooka: "A divergent synthesis of essentially enantiopure syn- and anti-propionate aldol adducts on the chiral 1,3,2-oxazaborolidin-5-one-promoted asymmetric aldol reaction followed by diastereoselective radical reduction"Bull.Chem.Soc.Jpn. 74. 1485-1495 (2001)
  • 説明: 「研究成果報告書概要(和文)」より
• [文献書誌] S.-i.Kiyooka: "Diastereoselective radical debromination approach toward divergent synthesis of syn-and anti-propionate units, coupled with enantioselective and/or diastereoselective Lewis acid-promoted aldol reactions"Tetrahedron : Asymmetry(An invited paper for the special issue on radical chemistry). 14. 2897-2910 (2003)
  • 説明: 「研究成果報告書概要(欧文)」より
• [文献書誌] S.-i.Kiyooka, K.A.Shahid, F.Goto, M.Okazaki, Y.Shuto: "Regulated-stereoselective construction of thirteen stereogenic centers necessary for the frame of (+)-discodermolide, based on iterative Lewis acid-promoted aldol reactions"J.Org.Chem.. 68. 7967-7978 (2003)
  • 説明: 「研究成果報告書概要(欧文)」より
• [文献書誌] S.-i.Kiyooka, H.Fujimoto, M.Mishima, S.Kobayashi, K.M.Uddin, Fujio: "Diphenylboron perchlorate as an efficient catalyst for self-and cross-condensation reactions of aldehydes having α-active hydrogens"Tetrahedron Lett.. 44. 927-930 (2003)
  • 説明: 「研究成果報告書概要(欧文)」より
• [文献書誌] K.A.Shahid, J.Mursheda, M.Okazaki, Y.Shuto, F.Goto, S.-i.Kiyooka: "A straightforward, highly stereoselective construction of eight stereogenic centers in (+)-discodermolide C1-C13 segment, based on a strategy of iterative aldol reactions"Tetrahedron Lett.. 43. 6377-6381 (2002)
  • 説明: 「研究成果報告書概要(欧文)」より
• [文献書誌] K.A.Shahid.Y.-N.Li, M.Okazaki.Y.Shuto.F.Goto, S.-i.Kiyooka: "A short synthesis of the C15-C21 segment of (+)-discodermolide, based on an asymmetric approach from achiral 2-methyl-1,3-propanediol to versatile enantiopure stereotriads"Tetrahedron Lett.. 43. 6373-6376 (2002)
  • 説明: 「研究成果報告書概要(欧文)」より
• [文献書誌] S.-i.Kiyooka, M.Shiinoki, K.Nakata, F.Goto: "A straightforward strategy toward the constraction of polypropionate frameworks, based on a sequence of diastereoselective Lewis acid-mediated aldol reaction and diastereoselective radical debromination reaction"Tetrahedron Lett.. 43. 5377-5380 (2002)
  • 説明: 「研究成果報告書概要(欧文)」より
• [文献書誌] S.-i.Kiyooka.Y.-N.Li, K.A.Shahid, M.Okazaki, Y.Shuto: "Versatile, high 2,4-syn dialkyl diastereoselection in the radical debromination of α-bromo-α-methyl-δ-valerolactones with tri-butyltin hydride and a catalytic amount of triethylborane"Tetrahedron Lett.. 42. 7299-7301 (2001)
  • 説明: 「研究成果報告書概要(欧文)」より
• [文献書誌] S.-i.Kiyooka, R.Fujiyama, T.Kawai, H.Fujimoto, K.Goh: "Is diphenylboronium perchlorate in nitromethane ionic?"Tetrahedron Lett.. 42. 4151-4153 (2001)
  • 説明: 「研究成果報告書概要(欧文)」より
• [文献書誌] S.-i.Kiyooka.K.A.Shahid, K.Murai, Y.-N.Li, M.Okazaki, Y.Shuto: "Asymmetric synthesis of a 3,4-syn homologous series of ethyl 3,5-dihydroxy-2,4-dimethyl-5-phenylpentanoates"Tetrahedron : Asymmetry. 12. 2343-2349 (2001)
  • 説明: 「研究成果報告書概要(欧文)」より
• [文献書誌] S.-i.Kiyooka K.A.Shahid: "A divergent synthesis of essentially enantiopure syn-and anti-propionate aldol adducts based on the chiral 1,3,2-oxazaborolidin-5-one-promoted asymmetric aldol reaction followed by diastereoselective radical reduction"Bull.Chem.Soc.Jpn.. 74. 1485-1495 (2001)
  • 説明: 「研究成果報告書概要(欧文)」より
• [文献書誌] K.A.Shahid et al.: "A straightforward, hightly stereoselective construction of eight stereogenic centers ----"Tetrahedron Lett.. 43. 6377-6381 (2002)
• [文献書誌] K.A.Shahid et al.: "A short synthesis of the C15-C21 segment of (+)-discodermolide, based on a ------"Tetrahedron Lett.. 43. 6373-6376 (2002)
• [文献書誌] S.-i.Kiyooka et al.: "A straightforward strategy toward the construction of polypropionate frameworks ---"Tetrahedron Lett.. 43. 5377-5380 (2002)
• [文献書誌] M.G.Ahmed et al.: "A convenient one pot synthesis of substituted and unsubstituted --------"Indian Journal of Chemistry, Section B. 41B(2). 368-371 (2002)
• [文献書誌] S.-i.Kiyooka et al.: "Diphenyl boron perchlorate as an efficient catalyst for self-and cross-condensation ---"
• [文献書誌] Kiyooka, S.-i. et al.: "Is diphenyl boronium perchlorate in nitromethane ionic?"Tetrahedron Lett.. 42. 4151-4153 (2001)
• [文献書誌] Kiyooka, S.-i. et al.: "Versatile, high 2,4-syn dialkyl diastereoselection in the radical debromination"Tetrahedron Lett.. 42. 7299-7301 (2001)
• [文献書誌] Kiyooka, S.-i. et al.: "Superior substrate control on diastereoselection in boric Lewis acid-promoted aldol reactions"Tetrahedron : Asymmetry. 12. 2343-2349 (2001)
• [文献書誌] Kiyooka, S.-i. et al.: "A divergent synthesis of essentially enantiopure syn -and anti-propionate aldol adducts"Bull. Chem. Soc. Jpn.. 74. 1485-1495 (2001)
• [文献書誌] Kiyooka,S.i. et al.: "Efficient enantio-and diastereoselective synthesis of enantiopure syn-α-bromo-β-hydroxy-α-methyl propionate"Tetrahedron : Asymmetry. 11. 1537-1542 (2000)
• [文献書誌] Kiyooka,S.i. et al.: "An efficient method for the synthesis of enantiopure 2,3-anti-propionate aldols"Tetrahedron Letters. 41. 2633-2637 (2000)
• [文献書誌] Kiyooka,s.-i. et al.: "A short and efficient synthesis of N-Cb8-galantinic acid under promoter control"Tetrahedron Letters. 41. 6599-6603 (2000)
• [文献書誌] Kiyooka,S.-i. et al.: "An effective extension of the polyacetate chain in the polyene macrolide antibiotic filipin III"Tetrahedron Letters. 41. 7511-7516 (2000)