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Synthesis 2006(18): 2993-2995  
DOI: 10.1055/s-2006-942544
SHORTPAPER
© Georg Thieme Verlag Stuttgart · New York

A Novel Method for the Introduction of Fluorine into the Purine 2-Position: Synthesis of 2-Fluoroadenosine and a Formal Synthesis of the Antileukemic Drug Fludarabine

Morten Brændvang, Lise-Lotte Gundersen*
Department of Chemistry, University of Oslo, P.O. Box 1033, Blindern, 0315 Oslo, Norway
Fax: +47(22)855507; e-Mail: l.l.gundersen@kjemi.uio.no;
Further Information

Publication History

Received 23 April 2006
Publication Date:
02 August 2006 (online)

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Abstract

A novel method for the introduction of fluorine in the purine 2-position is described and employed in the synthesis of a potential antimycobacterial compound. Also 2-fluoroadenosine has been synthesized for the first time from adenosine with perbenzo­ylated 2-nitroadenosine as a key intermediate. Mild reaction conditions are employed and few synthetic steps are required. The novel synthesis of fluoroadenosine can be regarded as a formal synthesis of the antileukemic drug fludarabine phosphate.

Key words

anticancer agents - fluorination - nitration - nucleosides - purines

    References

  • 1 Rosemeyer H. Chem. Biodiversity  2004,  1:  361 
    CrossrefPubMedGoogle Scholar
  • 2 Seela F. Ramzaeva N. Rosemeyer H. In Science of Synthesis   Vol. 16:  Yamamoto Y. Thieme; Stuttgart: 2004.  p.1945 ; and references therein
    Google Scholar
  • 3a Deghati PYF. Wanner MJ. Koomen G.-J. Tetrahedron Lett.  2000,  41:  1291 
    CrossrefGoogle Scholar
  • 3b Rodenko B. Koch M. Van der Burg AM. Wanner MJ. Koomen G.-J. J. Am. Chem. Soc.  2005,  127:  5957 
    CrossrefGoogle Scholar
  • 4a Wanner MJ. Von Frijtag Drabbe Künzel JK. Ijzerman AP. Koomen G.-J. Bioorg. Med. Chem. Lett.  2000,  10:  2141 
    CrossrefGoogle Scholar
  • 4b Rodenko B. Wanner MJ. Koomen G.-J. J. Chem. Soc., Perkin Trans. 1  2002,  1247 
    CrossrefGoogle Scholar
  • 5a Wanner MJ. Koomen G.-J. J. Chem. Soc., Perkin Trans. 1  2001,  1908 
    CrossrefGoogle Scholar
  • 5b Beukers MW. Wanner MJ. Von Frijtag Drabbe Künzel JK. Klaasse EC. Ijzerman AP. Koomen G.-J. J. Med. Chem.  2003,  46:  1492 
    CrossrefGoogle Scholar
  • 5c Wanner MJ. Koch M. Koomen G.-J. J. Med. Chem.  2004,  47:  6875 
    CrossrefGoogle Scholar
  • 6 Kuduk SD. DiPardo RM. Bock MG. Org. Lett.  2005,  7:  577 
    CrossrefGoogle Scholar
  • 7a Bakkestuen AK. Gundersen L.-L. Langli G. Liu F. Nolsøe JMJ. Bioorg. Med. Chem. Lett.  2000,  10:  1207 
    CrossrefGoogle Scholar
  • 7b Gundersen L.-L. Nissen-Meyer J. Spilsberg B. J. Med. Chem.  2002,  45:  1383 
    CrossrefGoogle Scholar
  • 7c Bakkestuen AK. Gundersen L.-L. Utenova BT. J. Med. Chem.  2005,  48:  2710 
    CrossrefGoogle Scholar
  • 7d Brændvang M. Gundersen L.-L. Bioorg. Med. Chem.  2005,  13:  6360 
    CrossrefGoogle Scholar
  • 8 Bauman JG, and Wirsching RC. inventors; PCT Int. Appl. WO 9412514,  .  Chem. Abstr. 1995, 122, 133691
  • 9 See for instance: Nabhan C. Gartenhaus RB. Tallman MS. Leukemia Res.  2004,  28:  429 
    CrossrefGoogle Scholar
  • For some recent examples of bioactive 2-fluoropurines, see:
  • 10a Qin X. Chen X. Wang K. Polin L. Kern ER. Drach JC. Gullen E. Cheng Y.-C. Zemlicka J. Bioorg. Med. Chem.  2006,  14:  1247 
    CrossrefGoogle Scholar
  • 10b He H. Zatorska D. Kim J. Aguirre J. Llauger L. She Y. Wu N. Immormino RM. Gewirth DT. Chiosis G. J. Med. Chem.  2006,  49:  381 
    CrossrefGoogle Scholar
  • 10c Takagi C. Sukeda M. Kim H.-S. Wataya Y. Yabe S. Kitade Y. Matsuda A. Shuto S. Org. Biomol. Chem.  2005,  3:  1245 
    CrossrefGoogle Scholar
  • 10d Ye S. Rezende M. Deng W.-P. Herbert B. Daly JW. Johnson RA. Kirk KL. J. Med. Chem.  2004,  47:  1207 
    CrossrefGoogle Scholar
  • 10e Hutchinson SA. Baker SP. Linden J. Scammells PJ. Bioorg. Med. Chem.  2004,  12:  4877 
    CrossrefGoogle Scholar
  • 11 Brown GA, Savory ED, Ouzman JVA, and Stoddart AM. inventors; PCT Int. Appl. WO 2005056571,  .  Chem. Abstr. 2005, 143, 60193
  • 12 Montgomery JA. J. Am. Chem. Soc.  1960,  82:  463 
    CrossrefGoogle Scholar