Development of New Silicon Tethers and Their Application to the Synthesis of Anti-HIV Nucleosides

• Project/Area Number: 13672203
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Chemical pharmacy
• Research Institution: HOKKAIDO UNIVERSITY
• Principal Investigator: SHUTO Satoshi Hokkaido Univ. Grad. School of Pharm. Sci., Associate Prof., 大学院・薬学研究科, 助教授 (70241346)
• Project Period (FY): 2001 – 2002
• Project Status: Completed (Fiscal Year 2002)
• Budget Amount: ¥4,000,000 (Direct Cost: ¥4,000,000); Fiscal Year 2002: ¥1,900,000 (Direct Cost: ¥1,900,000); Fiscal Year 2001: ¥2,100,000 (Direct Cost: ¥2,100,000)
• Keywords: Silicon tether / Ethynyl group / Radical reaction / Atom transfer / Anti-HIV agent / Nucleoside

Research Abstract

A novel radical method for the stereoselective introduction of an ethynyl group using ethynyldimethylsilyl (EDMS) or [2-(trimethylsilyl)ethynyl]dimethylsilyl (TEDMS) as the radical acceptor tethers has been developed. When a solution of EDMS or TEDMS ethers of trans-2-iodoindanoI was treated with Et_3B followed by tetrabutylammonium fluoride in toluene, atom transfer 5-exo-cyclization and subsequent elimination occurred to give cis-2-ethynylindanol in high yield. The method was shown to be useful in the introduction of an ethynyl group in various five and six-membered ring iodohydrins. Furthermore, 2'-deoxy-2'-C-ethynyluridine and cytidine, which were designed as novel anti-HIV nucleoside analogues, were readily synthesized using this method as the key step.

Research Products

• [Publications] M.Sukeda et al.: "A New Entry to the Stereoselective Introduction of an Ethynyl Group via Radical Reaction. Synthesis of a Potential Antimetabolite 2-Deoxy-2'-C-Ethynyluridine"Angew. Chem. Int. Ed. 41. 4748-4750 (2002)
  • Description: 「研究成果報告書概要(和文)」より
• [Publications] M.Sukeda et al.: "The First Radical Method for the Introduction of an Ethynyl Group Using a Silicon Tether and its Application to the Synthesis of 2 -Deoxy-2'-C-Ethynylnucleosides"J. Org. Chem. (in press).
  • Description: 「研究成果報告書概要(和文)」より
• [Publications] A.Tamura et al.: "Reversal of the α/β-Stereoselectivity in Lewis Acid-Promoted C-Glycosidation Using a Controlling Anomeric Effect : Highly α-and β-Selective Anomeric Allylation with Allyltrimethylsilane Based on the Conformational Restrlction Strategy"Angew. Chem. Int. Ed. (in press).
  • Description: 「研究成果報告書概要(和文)」より
• [Publications] M. Sukeda, S. Shuto, I. Sugimoto, S. Ichikawa, A. Matsuda: "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(欧文)」より
• [Publications] T. Kodama, S. Shuto, M. Nomura, A. Matsuda: "1'a Branched-chain sugar pyrimidine ribonucleosides from uridine. The first conversion of a natural nucleoside into 1'-substituted ribonucleosides"Chem. Eur. J.. 7. 2332-2340 (2001)
  • Description: 「研究成果報告書概要(欧文)」より
• [Publications] H. Abe, S. Shuto, S. Tamura, A. Matsuda: "An efficient method for preparing fully O-silylated pyranoses conformationally restricted in the unusual ^1C_4-form"Tetrahedron Lett.. 42. 6159-6161 (2001)
  • Description: 「研究成果報告書概要(欧文)」より
• [Publications] H. Abe, S. Shuto, A. Matsuda: "Highly a- and b-selective radical C-glycosylation reactions based on the conformational restriction strategy using a controlling anomeric effect. A study on the conformation-anomeric effect-stereoselectivity relationship in the anomcric radical reactions"J. Am. Chem. Soc.. 123. 11870-11882 (2001)
  • Description: 「研究成果報告書概要(欧文)」より
• [Publications] T. Kodama, S. Shuto, S. Ichikawa, A. Matsuda: "A Highly Stereoselective Samarium Diiodide-Promoted Aldol Reaction Using 1'-Phenylseleno-2'-Keto Nucleosides. Synthesis of 1'a-Branched Uridine Derivatives"J. Org. Chem.. 67. 7706-7715 (2002)
  • Description: 「研究成果報告書概要(欧文)」より
• [Publications] M. Sukeda, S. Ichikawa, A. Matsuda, S. Shuto: "A New Entry to the Stereoselective Introduction of an Ethynyl Group via Radical Reaction. Synthesis of a Potential Antimetabolite 2'-Deoxy-2'-C-Ethynyluridine"Angew. Chem. Int. Ed.. 41. 4748-4750 (2002)
  • Description: 「研究成果報告書概要(欧文)」より
• [Publications] S. Shuto, M. Kanazaki, I. Sugimoto, S. Ichikawa, Y. Nagasawa, Y. Ueno, H. Abe, N. Minakawa, M. Sukeda, T. Kodama, M. Nomura, A. Matsuda: "evelopment of new radical reactions with a vinylsilyl group and their application to the synthesis of branched-chain sugar nucleosides"Recent Advances in Nucleosides : Chemistry and Chemotherapy, Ed. By C. K. Chu, Elsevier. 21-55 (2002)
  • Description: 「研究成果報告書概要(欧文)」より
• [Publications] A. Tamura, H. Abe, A. Matsuda, S. Shuto: "Control of the a/b-Stereoselectivity in Lewis Acid- Promoted C-Glycosidation Using a Controlling Anomeric Effect Based on the Conformational Restriction Strategy"Angew. Chem. Int. Ed.. 42. 1021-1023 (2003)
  • Description: 「研究成果報告書概要(欧文)」より
• [Publications] M. Sukeda, S. Ichikawa, A. Matsuda, S. Shuto: "The First Radical Method for the Introduction of an Ethynyl Group Using a Silicon Tether and its Application to the Synthesis of 2'- Deoxy-2'-C-Ethynylnucleosides"J. Org. Chem.. in press..
  • Description: 「研究成果報告書概要(欧文)」より
• [Publications] M.Sukeda et al.: "A New Entry to the Stereoselective Introduction of an Ethynyl Group via Radical Reaction. Synthesis of a Potential Antimetabolite 2-Deoxy-2'-C-Ethynyluridine"Angew.Chem.Int.Ed. 41. 4748-4750 (2002)
• [Publications] M.Sukeda et al.: "The First Radical Method for the Introduction of an Ethynyl Group Using a Silicon Tether and its Application to the Synthesis of 2 -Deoxy-2'-C-Ethynylnucleosides"J.Org.Chem. (in press).
• [Publications] A.Tamura et al.: "Reversal of the α/β-Stereoselectivity in Lewis Acid-Promoted C-Glycosidation Using a Controlling Anomeric Effect : Highly α-and β-Selective Anomeric Allylation with Allyltrimethylsilane Based on the Conformational Restriction Strategy"Angew.Chem.Int.Ed. (in press).
• [Publications] T.Kodama, et al.: "l'α-Branched-chain sugar pyrimidine ribonucleosides from uridine. The first conversion of a natural nucleoside into l'-substituted ribonucleosides"Chem. Eur. J.. 7. 2332-2340 (2001)
• [Publications] H.Abe, et al.: "An efficient method for preparing fully O-silylated pyranoses conformationally restricted in the unusual 'C_4-form"Tetrahedron Lett.. 42. 6159-6161 (2001)
• [Publications] H.Abe, et al.: "Highly α- and β-selective radical C-glycosylation reactions based on the conformational restriction strategy using a controlling anomeric effect. A study on the conformation-anomeric effect-stereoselectivity relationship in the anomeric radical reactions"J. Am. Chem. Soc.. 123. 11870-11882 (2001)