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A Noven Radical Ring-Enlargement Reaction : The Reaction Mechanism and the Medicinal Chemical Application

Research Project

Project/Area Number 11672095
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Chemical pharmacy
Research InstitutionHokkaido University

Principal Investigator

SHUTO Satoshi  Graduate School of Pharmaceutical Sciences, Associate Professor, 大学院・薬学研究科, 助教授 (70241346)

Project Period (FY) 1999 – 2000
Project Status Completed (Fiscal Year 2000)
Budget Amount *help
¥3,400,000 (Direct Cost: ¥3,400,000)
Fiscal Year 2000: ¥1,700,000 (Direct Cost: ¥1,700,000)
Fiscal Year 1999: ¥1,700,000 (Direct Cost: ¥1,700,000)
KeywordsC-glycoside / nucleoside / radical reaction / reaction mechanism / ring-enlargement / silicon tether / Tamao oxidation / transition state / ラジカル / ケイ素 / IP3 / カルシウム
Research Abstract

We developed a regio-and stereoselective method for introducing 1-hydroxyethyl, 2-hydroxyethyl, and vinyl groups at the position β to a hydroxyl group in halohydrins or α-phenylselenoalkanols using an intramolecular radical cyclization reaction with a dimethyl-or diphenylvinylsilyl group as a temporary connecting radical-acceptor tether (Scheme 14). Thus, when a vinylsilyl ether of halohydrins or α-phenylselenoalkanols was subjected to the radical reaction with Bu_3SnH/AIBN, the selective introduction of both 1-hydroxyethyl and 2-hydroxyethyl groups can be achieved, depending on the concentration of Bu_3SnH in the reaction system, via a 5-exo-cyclization intermediate or a 6-endo-cyclization intermediate, respectively, after oxidative ring-cleavage by treating the cyclization products under Tamao oxidation conditions. A vinyl group can also be introduced by photo-irradiating the vinylsilyl ether in the presence of (Bu_3Sn)_2, and then treating the resulting atom-transfer 5-exo-cyclization product with fluoride ion. The mechanistic studies showed that the kinetically favored 5-exo-cyclized radical was trapped when the concentration of Bu_3SnH was high enough. At lower concentrations of Bu_3SnH and higher reaction temperatures, the 5-exo-cyclized radical rearranged into the more stable ring-enlarged 4-oxa-3-silacyclohexyl radical, which was then trapped with Bu_3SnH.The ring-enlarging rearrangement was experimentally proved to occur via a pentavalent-like silicon-bridging transition state. This radical reaction with a vinylsilyl tether has been successfully applied to the synthesis of 4'-branched-chain sugar nucleosides as a nucleoside unit for antisense studies and also for potent antiviral nucleosides. C-glycosides trisphosphates as potent IP_3-receptor ligands were also synthesized using the radical reaction as the key step.

Report

(3 results)
  • 2000 Annual Research Report   Final Research Report Summary
  • 1999 Annual Research Report
  • Research Products

    (38 results)

All Other

All Publications (38 results)

  • [Publications] I.Sugimoto, et al.: "Synthesis of 4'α-branched thymidines as a new type of aniviral agent."Bioorg.Med.Chem.Lett.. 9. 385-388 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] Y.Yahiro, et al.: "Synthesis of C-glycosides via radical cyclization reactions with a vinylsilyl tether. Control of the reaction course by a change in the conformation of the pyranose ring due to steric repulsion between adjacent bulky protecting groups."Tetrahedron Lett.. 40. 5527-5531 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] S.Sugimoto, et al.: "A one-pot method for the stereoselective introduction of a vinyl group via an atom transfer radical cyclization reaction with a diphenylvinylsilylgroup as a temporary connecting tether. Synthesis of 4'α-C-vinylthymidine, a potent antiviral nucleoside."J.Org.Chem.. 64. 7153-7157 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] S.Sugimoto, et al.: "Kinetics of a novel 1,2-rearrangement reaction of β-silyl radicals. The ring-expansion of (3-oxa-silacyclopentyl) methyl radical into 4-oxa-3-silacyclohexyl radical is irreversible."Synlett. 1766-1768 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] M.Kashiwayanagi, et al.: "Inward current responses to IP_3 and adenophostin-analogues in turtle olfactory sensory neurons."Eur.J.Neurosci.. 12. 606-612 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] S.Shuto, et al.: "Mechanistic study of the ring-enlargement reaction of (3-oxa-2-silacyclopentyl) methyl radicals into 4-oxa-3-silacyclohexyl radicals. Evidence for a pentavalent silicon-bridging radical transition state in 1,2-rearrangement reactions of β-silyl radicals."J.Am.Chem.Soc.. 122. 1343-1351 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] M.Kanazaki, et al.: "Highly nuclease-resistant phosphodiester-type oligodeoxynucleotides containing 4'α-C-aminoalkylthymidines form thermally stable duplexes with DNA and RNA. A candidate for potent antisense molecules."J.Am.Chem.Soc.. 122. 2422-2432 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] R.D.Marwood, et al.: "Convergent synthesis of adenophostin A analogues via a base replacement strategy."Chem.Commun.. 219-220 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] H.Abe, et.al.: "Synthesis of the C-glycosidic analog of adenophostin A, a potent IP_3 receptor agonist, using a temporary silicon-tethered radical coupling reaction as the key step."Tetrahedron Lett.. 41. 2391-2394 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] T.Kodama, et.al.: "Synthesis of a 1'α-phenylselenouridine derivative as a synthetic precursor for various 1'-modified nucleosides, via enolization at the 1'-position of 3',5'-O-TIPDS-2'-ketouridine."Tetrahedron Lett.. 41. 3643-3646 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] S.Shuto, et al.: "Stereoselective synthesis of α-and β-C-glucosides via radical cyclization with an allylsilyl tether. Control of the stereoselectivity by changing the conformation of the pyranose ring."Tetrahedron Lett.. 41. 4151-4155 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] H.Abe, et al.: "Synthesis of the C-glycosidic analog of adenophostin A and its uracil congener as potential IP_3 receptor ligands. Stereoselective construction of the C-glycosidic structure by a temporary silicon-tethered radical coupling reaction."J.Org.Chem.. 65. 4315-4325 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] S.Shuto, et al.: "Synthesis of 3,7-anhydro-D-glycero-D-ido-octitol 1,5,6-trisphosphate as an IP_3 receptor ligand using a radical cyclization reaction with a vinylsilyl tether as the key step. Conformational restriction strategy using steric repulsion between adjacent bulky protecting groups on a pyranose ring."J.Org.Chem.. 65. 5547-5557 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] M.Sukeda, et al.: "Synthesis of pyrimidine 2'-deoxy-ribonucleosides branched at the 2'-position via radical atom-transfer cyclization reaction with a vinylsilyl group as a radical-acceptor tether"J.Org.Chem.. 65. 8988-8996 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] T.Kodama, et al.: "Synthesis and radical reaction of 1'-phenylselenonucleosides."Nucleic Acid Symposium series. 44. 109-110 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] T.Kodama, et al.: "I'α-Branched-chain sugar pyrimidine ribonucleosides from uridine. The first conversion of a natural nucleoside into 1'-substituted ribonucleosides"Chem.Eur.J.. (in press).

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] 周東智 他: "ビニルシリル基をテザーに用いるラジカル反応:C2ユニットの立体選択的導入法の開発と5価ケイ素ラジカル遷移状態を経由する新規ラジカル環拡大反応"有合化. (印刷中).

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] V.Correa, et al.: "Structural determinants of adenophostin A activity at inositol trisphosphate receptors."Molecular Pharmacol.,. (in press).

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2000 Final Research Report Summary
  • [Publications] M.Kashiwayanagi, et al.: "Inward current responses to IP_3 and adenophostin-analogues in turtle olfactory sensory neurons."Eur.J.Neurosci.. 12. 606-612 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] S.Shuto, et al.: "Mechanistic study of the ring-enlargement reaction of (3-oxa-2-silacyclopentyl)methyl radicals into 4-oxa-3-silacyclohexyl radicals.Evidence for a pentavalent silicon-bridging radical transition state in 1,2-rearrangement reactions of β-silyl radicals."J.Am.Chem.Soc.. 122. 1343-1351 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] M.Kanazaki, et al.: "Highly nuclease-resistant phosphodiester-type oligodeoxynucleotides containing 4'α-C-aminoalkylthymidines form thermally stable duplexes with DNA and RNA.A candidate for potent antisense molecules."J.Am.Chem.Soc.. 122. 2422-2432 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] R.D.Marwood, et.al.: "Convergent synthesis of adenophostin A analogues via a base replacement strategy."Chem.Commun.. 219-220 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] H.Abe, et.al.: "Synthesis of the C-glycosidic analog of adenophostin A, a potent IP_3 receptor agonist, using a temporary silicon-tethered radical coupling reaction as the key step."Tetrahedron Lett.. 41. 2391-2394 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] T.Kodama, et al.: "Synthesis of a 1'α-phenylselenouridine derivative as a synthetic precursor for various 1'-modified nucleosides, via enolization at the 1'-position of 3',5'-O-TIPDS-2'-ketouridine."Tetrahedron Lett.. 41. 3643-3646 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] S.Shuto, et al.: "Stereoselective synthesis of α-and β-C-glucosides via radical cyclization with an allylsilyl tether. Control of the stereoselectivity by changing the conformation of the pyranose ring."Tetrahedron Lett.. 41. 4151-4155 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] H.Abe, et al.: "Synthesis of the C-glycosidic analog of adenophostin A and its uracil congener as potential IP_< 3 > receptor ligands. Stereoselective construction of the C-glycosidic structure by a temporary silicon-tethered radical coupling reaction."J.Org.Chem.. 65. 4315-4325 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] S.Shuto, et al.: "Synthesis of 3,7-anhydro-D-glycero-D-ido-octitol 1,5,6-trisphosphate as an IP_3 receptor ligand using a radical cyclization reaction with a vinylsilyl tether as the key step. Conformational restriction strategy using steric repulsion between adjacent bulky protecting groups on a pyranose ring."J.Org.Chem.. 65. 5547-5557 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] M.Sukeda, et al.: "Synthesis of pyrimidine 2'-deoxy-ribonucleosides branched at the 2'-position via radical atom-transfer cyclization reaction with a vinylsilyl group as a radical-acceptor tether"J.Org.Chem.. 65. 8988-8996 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] T.Kodama, et al.: "Synthesis and radical reaction of 1'-phenylselenonucleosides."Nucleic Acid Symposium series. 44. 109-110 (2000)

    • Related Report
      2000 Annual Research Report
  • [Publications] T.Kodama, et al.: "1'α-Branched-chain sugar pyrimidine ribonucleosides from uridine. The first conversion of a natural nucleoside into 1'-substituted ribonucleosides"Chem.Eur.J.. (in press).

    • Related Report
      2000 Annual Research Report
  • [Publications] 周東智. 他: "ビニルシリル基をテザーに用いるラジカル反応:C2 ユニットの立体選択的導入法の開発と5価ケイ素ラジカル遷移状態を経由する新規ラジカル環拡大反応"有合化. 59(印刷中).

    • Related Report
      2000 Annual Research Report
  • [Publications] V.Correa, et al.: "Structural determinants of adenophostin A activity at inositol trisphosphate receptors."Molecular Pharmacol.. (in press).

    • Related Report
      2000 Annual Research Report
  • [Publications] Y.Yahiro, et al.: "Synthesis of C-glycosides via radical cyclization reactions with a vinylsilyl tether"Tetrahedron Lett.. 40. 5527-5531 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] I.Sugimoto, et al.: "A one-pot method for the stereoselective introduction of a vinyl group via an atom transfer radical cyclization reaction"J. Org. Chem.. 64. 7153-7157 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] I.Sugimoto, et al.: "Kinetics of a novel 1,2-rearrangement reaction of β-silyl radicals"Synlett. 1766-1768 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] I.Sugimoto, et al.: "Mechanistic study of the ring-enlargement reaction of (3-oxa-2-silacyclopentyl)methyl radicals"J. Am. Chem. Soc.. (in press).

    • Related Report
      1999 Annual Research Report
  • [Publications] M.Kanazaki, et al.: "Highly nuclease-resistant phosphodiester-type oligodeoxynucleotides containing 4'α-C-aminoalkylthymidines"J. Am. Chem. Soc.. (in press).

    • Related Report
      1999 Annual Research Report
  • [Publications] H.Abe, et al.: "Synthesis of the C-glycosidic analog of adenophostin A, a potent IP_3 receptor agonist"Tetrahedron Lett.. (in press).

    • Related Report
      1999 Annual Research Report

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Published: 1999-04-01   Modified: 2016-04-21  

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