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Synthetic Study on HMG-CoA Reductase Inhibitors

Research Project

Project/Area Number 05453135
Research Category

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

Allocation TypeSingle-year Grants
Research Field Synthetic chemistry
Research InstitutionTokyo Institute of Technology

Principal Investigator

HIYAMA Tamejiro  Tokyo Institute of Technology, Research Laboratory of Resources Utilization, Professor, 資源化学研究所, 教授 (90026295)

Co-Investigator(Kenkyū-buntansha) KUSUMOTO Tetsuo  Sagami Chemical Research Center, Research Fellow, 副主任研究員
Project Period (FY) 1993 – 1994
Project Status Completed (Fiscal Year 1994)
Budget Amount *help
¥7,300,000 (Direct Cost: ¥7,300,000)
Fiscal Year 1994: ¥2,600,000 (Direct Cost: ¥2,600,000)
Fiscal Year 1993: ¥4,700,000 (Direct Cost: ¥4,700,000)
KeywordsHMG-CoA Reductase Inhibitor / Asynmetric Reduction / Olefin Synthesis / Hydrosilylation / Cross-Coupling / Hydrometalation / 不斉合成
Research Abstract

Since compactin and mevionlin were shown to be highly potent inhibitors of 3-hydroxy-3-methylglutaryl Coenzyme A (HMG Co-A) reductase, a number of synthetic analogs have been designed and sythesized to improve activity and suppress side effects. We have studied general synthetic methods which sllow us to prepare a variety of the target molecules including NK-104, all of which consist of an aromatic part and a trans-beta-hydroxy-delta-lactone moiety, both connected by trans-1,2-ethylidene bridge. Our retrosynthetic anslysis led to three novel strategies.
(1) Asymmetric Reduction of 3,5-Diketo Esters
An ester of 7-aryl-substituted 3,5-dioxo-6-hexenoic acid and a chiral alcohol containing a naphthyl group was reduced with diisobutylaluminium hydride to give a 3-hydroxy 5-keto ester with an isomer ratio of>95 : 5. Subsequent syn-reduction with Et_2BOMe-NaBH_4, hydrolysis and lactonization gave rise to the target of high enantiomeric excess.
(2) Olefination Strategy
Olefination of 6-oxo-3,5-syn-dihydroxyhexanoate with Li(ArCHPOPh_2) was found to be an alternative route to the target compounds. Thus, the aldehyde of correct absolute configuration was prepared from diisopropyl D-tartrate by condensation with the dianion of t-butyl acetoacetate, stereoselective reduction, protection of 1,3-diols, followed by gylcol cleavage.
(3) Hydrometalation-Cross-Coupling Strategy
Palladium-catalyzed cross-coupling reaction of organosilicon compounds was successfully applied to t-butyl (3R,5S)-3,5-isopropylidenedioxy-6-heptynoate, which was prepared by chemical synthetic elaboration from diethyl L-tartrate, resolution, or asymmetric reduction of an acetylenic ketone with baker's yeast. Hydrosilylation of the acetylene with HSiMe_2Cl followed by Pd-catalyzed cross-coupling in the presence of tetrabutylammonium fluoride afforded the desired compound. The same transformation was achieved using 9-BBN or disiamylborane as the hydrometalating reagent.

Report

(3 results)
  • 1994 Annual Research Report   Final Research Report Summary
  • 1993 Annual Research Report
  • Research Products

    (21 results)

All Other

All Publications (21 results)

  • [Publications] Kyoko TAKAHASHI: "A New Synthesis of HMG-CoA Reductase Inhibitor NK-104 Through Hydrosilylation-Cross Coupling Reaction" Tetrahedorn Letters. 34. 8263-8266 (1993)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1994 Final Research Report Summary
  • [Publications] Mahammad H.ANSARI: "Synthesis of Optically Active t-Butyl (3R,5S)-3,5-Isopropylidenedioxy-6-heptynoate Through Baker's Yeast Reduction of Methyl 3-Oxo-4-pentynoate" Tetrahedorn Letters. 34. 8271-8274 (1993)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1994 Final Research Report Summary
  • [Publications] Tamejiro HIYAMA: "Stereoselective Reduction of β,δDiketo Esters.A Novel Strategy for the Synthesis of Artificial HMG-CoA Reductase Inhibitors" Bull.Chem.Soc.Jpn.68. 350-363 (1995)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1994 Final Research Report Summary
  • [Publications] Tamejiro HIYAMA: "Synthesis of Artificial HMG-CoA Reductase inhibitors Based on the Olefination Strategy" Bull.Chem.Soc.Jpn.68. 364-372 (1995)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1994 Final Research Report Summary
  • [Publications] Tamejiro HIYAMA: "Novel Synthetic Strategy for HMG-CoA Reductase Inhibitors" Pure & Appl.Chem.67(in press). (1995)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1994 Final Research Report Summary
  • [Publications] 宮地伸英: "HMG-CoA還元酵素阻害剤の合成" 有機合成化学協会誌. 53(in press). (1995)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1994 Final Research Report Summary
  • [Publications] Kyoko TAKAHASHI: "A New Synthesis of HMG-CoA Reductase Inhibitor NK-104 Through Hydrosilylation-Cross Coupling Reaction" Tetrahedorn Letters. 34. 8263-8266 (1993)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1994 Final Research Report Summary
  • [Publications] Nobuhide Miyachi: "A Novel Synthetic Method of HMG-CoA Reductase Inhibitor NK-104 Via A Hydroboration-Cross Coupling Sequence" Tetrahedorn Letters. 34. 8267-8270 (1993)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1994 Final Research Report Summary
  • [Publications] Mahammad H.ANSARI: "Synthesis of Optically Active t-Butyl (3R,5S)-3,5-Isopropylidenedioxy-6-heptynoate Through Baker's Yeast Reduction of Methyl 3-Oxo-4-pentynoate" Tetrahedorn Letters. 34. 8271-8274 (1993)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1994 Final Research Report Summary
  • [Publications] Tamejiro HIYAMA: "Stereoselective Reduction of beta, delta-Diketo Esters. A Novel Strategy for the Synthesis of Artificial HMG-CoA Reductase Inhibitors" Bull.Chem.Soc.Jpn.68. 350-363 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1994 Final Research Report Summary
  • [Publications] Tamejiro HIYAMA: "Synthesis of Artificial HMG-CoA Reductase Inhibitors Based on the Olefination Strategy" Bull.Chem.Soc.Jpn.68. 364-372 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1994 Final Research Report Summary
  • [Publications] Tamejiro HIYAMA: "Novel Synthetic Strategy for HMG-CoA Reductase Inhibitors" Pure & Appl. Chem. 67, (in press). (1995)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1994 Final Research Report Summary
  • [Publications] Nobuhide MIYACHI: "Syntheses of HMG-CoA Reductase Inhibitors" Yuki Gosei Kyokai Shi. 53, (in press). (1995)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1994 Final Research Report Summary
  • [Publications] Tamejiro HIYAMA: "Stereoselective Reduction of β,δ-Diketo Esters. A Novel Strategy for the Synthesis of Artificial HMG-CoA Reductase Inhibitors" Bull.Chem.Soc.Jpn.68. 350-363 (1995)

    • Related Report
      1994 Annual Research Report
  • [Publications] Tamejiro HIYAMA: "Synthesis of Artificial HMG-Co Reductase Inhibitors Based on the Olefination Strategy" Bull.Chem.Soc.Jpn.68. 364-372 (1995)

    • Related Report
      1994 Annual Research Report
  • [Publications] Tamejiro HIYAMA: "Novel Synthetic Strategy for HMG-CoA Reductase Inhibitors" Pure & Appl.Chem.67(in press). (1995)

    • Related Report
      1994 Annual Research Report
  • [Publications] 宮地伸英: "HMG-CoA還元酵素阻害剤の合成" 有機合成化学協会誌. 53(in press). (1995)

    • Related Report
      1994 Annual Research Report
  • [Publications] T.Minami: "Stereoselective Reduction of β,δ-Diketo Esters Derived from Tartaric Add.A Facile Route to Optically Active 6-Oxo-3,5-syn-isopropylidenedioxyhexanoate,a Versatile Synthetic Intermediate of Artificial HMG-CoA Reductase Inhibitors" Tetrahedron Letters. 34. 513-516 (1993)

    • Related Report
      1993 Annual Research Report
  • [Publications] K.Takahashi: "A New Synthesis of HMG-CoA Reductase Inhibitor NK-104 through Hydrosilylation-Cross Coupling Reaction" Tetrahedron Letters. 34. 8263-8266 (1993)

    • Related Report
      1993 Annual Research Report
  • [Publications] N.Miyachi: "A Novel Synthstic Method of HMG-CoA Reductase Inhibitor NK-104 via a Hydroboration-Cross Coupling Reaction" Tetrahedron Letters. 34. 8267-8270 (1993)

    • Related Report
      1993 Annual Research Report
  • [Publications] M.H.Ansari: "Synthesis of Optically Active t-Butyl(3R,5S)-3,5-isopropylidenedioxy-6-heptynoate through Baker's Yeast Reduction of Methyl3-Oxo-4-pentynoate" Tetrahedron Letters. 34. 8271-8274 (1993)

    • Related Report
      1993 Annual Research Report

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Published: 1993-04-01   Modified: 2016-04-21  

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