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

doi:10.1055/s-2006-942544

SHORTPAPER

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;

Abstract

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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

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References

1 Rosemeyer H. Chem. Biodiversity 2004, 1: 361

2 Seela F. Ramzaeva N. Rosemeyer H. In Science of Synthesis Vol. 16: Yamamoto Y. Thieme; Stuttgart: 2004. p.1945 ; and references therein

3a Deghati PYF. Wanner MJ. Koomen G.-J. Tetrahedron Lett. 2000, 41: 1291

3b Rodenko B. Koch M. Van der Burg AM. Wanner MJ. Koomen G.-J. J. Am. Chem. Soc. 2005, 127: 5957

4a Wanner MJ. Von Frijtag Drabbe Künzel JK. Ijzerman AP. Koomen G.-J. Bioorg. Med. Chem. Lett. 2000, 10: 2141

4b Rodenko B. Wanner MJ. Koomen G.-J. J. Chem. Soc., Perkin Trans. 1 2002, 1247

5a Wanner MJ. Koomen G.-J. J. Chem. Soc., Perkin Trans. 1 2001, 1908

5b Beukers MW. Wanner MJ. Von Frijtag Drabbe Künzel JK. Klaasse EC. Ijzerman AP. Koomen G.-J. J. Med. Chem. 2003, 46: 1492

5c Wanner MJ. Koch M. Koomen G.-J. J. Med. Chem. 2004, 47: 6875

6 Kuduk SD. DiPardo RM. Bock MG. Org. Lett. 2005, 7: 577

7a Bakkestuen AK. Gundersen L.-L. Langli G. Liu F. Nolsøe JMJ. Bioorg. Med. Chem. Lett. 2000, 10: 1207

7b Gundersen L.-L. Nissen-Meyer J. Spilsberg B. J. Med. Chem. 2002, 45: 1383

7c Bakkestuen AK. Gundersen L.-L. Utenova BT. J. Med. Chem. 2005, 48: 2710

7d Brændvang M. Gundersen L.-L. Bioorg. Med. Chem. 2005, 13: 6360

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

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

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

10c Takagi C. Sukeda M. Kim H.-S. Wataya Y. Yabe S. Kitade Y. Matsuda A. Shuto S. Org. Biomol. Chem. 2005, 3: 1245

10d Ye S. Rezende M. Deng W.-P. Herbert B. Daly JW. Johnson RA. Kirk KL. J. Med. Chem. 2004, 47: 1207

10e Hutchinson SA. Baker SP. Linden J. Scammells PJ. Bioorg. Med. Chem. 2004, 12: 4877

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