ORGANIC
LETTERS
2007
Vol. 9, No. 24
5007-5009
A Concise Synthesis of 4
Nucleosides
′-Fluoro
Seongmin Lee, Chayasith Uttamapinant, and Gregory L. Verdine*
Department of Chemistry and Chemical Biology, HarVard UniVersity,
Cambridge, Massachusetts 02138
gregory_Verdine@harVard.edu
Received September 11, 2007
ABSTRACT
Various 4′-F nucleosides have been prepared in only two to three steps via sequential bromination and fluorination of ribofuranoses or
nucleosides.
Nucleoside analogues are frequently used to inhibit DNA
biosynthesis, a process that is essential for cell growth and
viral replication.1 Substitution of hydrogen atoms for fluorine
has been extensively employed in the design of such
analogues, as this can dramatically affect the electronic
structure of a nucleoside without significantly altering its
size and shape.2 One such class of analogues that has received
attention of late is 4′-fluoro nucleosides. Nucleocidin,3 5′-
deoxy-4′,5-difluorouridine,4 4′-fluoroadenosine,5 and 2′-
deoxy-4′-fluorothimidine6 have been synthesized and tested
for biological activity. Access to a broader repertoire of 4′-
fluoronucleosides has been significantly hampered by the
lengthy synthetic routes (8 to 10 steps) employed to obtain
these derivatives, and also by the low overall yields of
product. Improved synthetic pathways would thus improve
access to the potentially important 4′-F nucleoside class for
biological studies. Herein, we describe two new and highly
efficient synthetic routes for 4′-F nucleosides, with sequential
bromination and fluorination being used as key reactions in
both processes.
Previous synthesis of 4′-F nucleosides3-5 employed io-
dofluorination of a nucleoside 4′-exo-olefin followed by
hydroxide ion displacement of the iodine, which produces
mixtures of 4′-epimers that can be difficult to separate. Our
synthetic strategy avoids this problem by taking advantage
of bromination and fluorination on nucleosides or 1-O-acetyl-
2,3,5-tri-O-benzoyl-â-D-ribose (Scheme 1).
(1) (a) Huryn, D. M.; Okabe, M. Chem. ReV. 1992, 92, 1745. (b) Patani,
G. A.; LaVoie, E. J. Chem. ReV. 1996, 96, 3147.
(2) (a) Michel, D.; Schlosser, M. Tetrahedron 2000, 56, 4523. (b)
Agrofoglio, L.; Suhas, E.; Farese, A.; Condom, R.; Guedj, R. Tetrahedron
1994, 50, 10611. (c) Scharer, O. D.; Verdine, G. L. J. Am. Chem. Soc.
1995, 117, 10781.
(3) (a) Jenkins, I. D.; Verheyden, J. P. H.; Moffat, J. G. J. Am. Chem.
Soc. 1971, 93, 4323. (b) Jenkins, I. D.; Verheyden, J. P. H.; Moffat, J. G.
J. Am. Chem. Soc. 1976, 98, 3346.
Sequential photobromination and fluorination has been
used to prepare fluorinated carbohydrate derivatives,7 but the
(4) Ajmera, S.; Bapat, A. R.; Stephanian, E.; Danenberg, P. V. J. Med.
Chem. 1988, 31, 1094.
(5) Guillerm, D.; Muzard, M.; Allart, B.; Guillerm, G. Bioorg. Med.
Chem. Lett. 1995, 5, 1455.
(7) (a) McCarter, J. D.; Withers, S. G. J. Am. Chem. Soc. 1996, 118,
241. (b) Hartman, M. C. T.; Coward, J. K. J. Am. Chem. Soc. 2002, 124,
10036. (c) Ferrier, R. J.; Haines, S. R. J. Chem. Soc., Perkin Trans. I 1984,
1675.
(6) Jung, M. E.; Toyota, A. J. Org. Chem. 2001, 66, 2624.
10.1021/ol702222z CCC: $37.00
© 2007 American Chemical Society
Published on Web 11/02/2007