A. Choudhury et al. / Tetrahedron Letters 44 (2003) 247–250
249
nitrile: dichloroethane, almost identical isolated desired
product yield (9, 33%) along with a 13% of the unde-
sired N7b product were obtained. Comparing the
stereodirecting effect of 5-t-BDPS protecting group ver-
sus 5-p-methylbenzoyl on the glycosylation step6
(CH3CN, rt, 16 h, N9/b:N9/a=5:1, N7b=10–15%,
Ref. 6), it is safe to say that the steric bulk of the
5-protecting group has a minimal influence on the
topology of glycosylation step under similar reaction
conditions. The t-butyldiphenylsilyl protecting group
was removed using TBAF/THF and treatment of the
crude with NH3/MeOH at 100°C for 18 h generated
F-ddA (1) in 55% overall yield in two steps and in a
one-pot sequence.
Driscoll, J. S.; Marquez, V. E. Tetrahedron Lett. 1998,
39, 1657.
5. (a) Okabe, M.; Sun, R.-C.; Zenchoff, G. B. J. Org.
Chem. 1991, 56, 4392; (b) Wysocki, R. J., Jr.; Siddiqui,
M. A.; Barchi, J. J., Jr.; Driscoll, J. S.; Marquez, V. E.
Synthesis 1991, 1005.
6. Jin, F.; Wang, D.; Confalone, P. N.; Pierce, M. E.;
Wang, Z.; Xu, G.; Choudhury, A.; Nguyen, D. Tetra-
hedron Lett. 2001, 42, 4787 and references cited therein.
7. (a) Hanessian, S.; Murray, P.; Sahoo, S. P. Tetrahedron
Lett. 1985, 26, 5623 and references cited therein; (b)
Vedejs, E.; Engler, D. A.; Telschow, J. E. J. Org. Chem.
1978, 43, 188.
8. Card, P. J. J. Org. Chem. 1983, 48, 393.
9. Giri, I.; Bolon, P. J.; Chu, C. K. Nucleosides Nucleotides
In conclusion we have demonstrated that the hydroxy
lactone 2 (obtained from commercially available 4 in
two short steps), can be converted to fluorolactone 5 in
high yield and selectivity. The subsequent glycosylation
with silylated base followed by deprotection of t-
TBDPS group and subsequent amination generated
F-ddA. With several asymmetric enolate oxidation pro-
tocols in literature and availability of DAST substi-
tutes, this sequence presents a promising future for
F-ddA synthesis.
1996, 183.
10. Davis, F. A.; Haque, S. M.; Ulatowski, T. G.; Towson,
J. C. J. Org. Chem. 1986, 51, 2402.
11. Reddy, D. R.; Thornton, E. R. J. Chem. Soc., Chem.
Commun. 1992, 2, 172.
12. Rubottom, G. A.; Gruber, J. M.; Juve, H. D., Jr.;
Charleson, D. A. Org. Synth. 1986, 64, 118.
13. Spectral data for compound 5: (3S,5S)-3-fluoro-5-(tert-
butyldiphenylsiloxy)pentan-4-olide (5): white solid, mp
101°C; 1H NMR (CDCl3): l 7.68–7.64 (m, 4H), 7.47–
7.38 (m, 6H), 5.25(dt, J=8.8 and 51.28 Hz, 1H), 4.53–
4.47 (m, 1H), 3.92 (ddd, J=1.26, 3.53 and 11.62 Hz,
1H), 3.73 (dd, J=11.62, 3.79 Hz, 1H), 2.71–2.62 (m,
1H), 2.59–2.45 (m, 1H), 1.06 (s, 3H); 13C NMR
(CDCl3): l 171.2 (d, J=21.06 Hz), 135.6, 135.5, 132.7,
132.4, 130, 129.97, 127.9, 85.8 (d, J=192.8 Hz), 76.3 (d,
J=6.13 Hz), 63.9, 30.3 (d, J=19.74 Hz), 26.7, 19.2; 19F
NMR (CDCl3): l −193.5 (ddd, J=6.88, 24.66 and 51.63
Hz). HRMS calcd for C21H25O3FSi [M+H] 373.1635,
found 373.1636.
Acknowledgements
This paper is dedicated to Professor Ralph F.
Hirschmann on the occasion of his 80th birthday. We
thank Tom Neiss and Barbara Stephens for analytical
support. This work was carried out at DuPont
Pharmaceuticals.
14. (a) Jpn. Kokai Tokkyo Koho, 05247082, 1993; (b) Mc-
Atee, J. J.; Schinazi, R. F.; Liotta, D. C. J. Org. Chem.
1998, 63, 2161.
References
15. Ref. 5a and references cited therein.
16. (a) Tann, C. H.; Brodfuehrer, P. R.; Brundidge, D. A.;
Sapino, C.; Howell, H. G. J. Org. Chem. 1985, 50, 3644;
(b) Howell, H. G.; Brodfuehrer, P. R.; Brundidge, S. P.;
Benigni, D. A.; Sapino, C. J. Org. Chem. 1988, 53, 85.
17. (a) Montero, J. L.; Winum, J. Y.; Leydet, A.; Kamal,
M.; Pavia, A. A.; Roque, J. P. Carbohydr. Res. 1997,
297, 175; (b) b-selective glycosylation has been achieved
with bulky trityl group (Ref. 5a) and also t-
butyldiphenylsilylsilyl as the 5%-substituents, see: Giri, I.;
Bolon, P. J.; Chu, C. K. Nucleosides Nucleotides 1996,
183.
1. (a) Graul, A.; Silvestre, J.; Castaner, J. Drug of the
Future 1998, 23, 1176; (b) Marquez, V. E.; Tseng, C.
K.-H.; Kelly, J. A.; Mitsuya, H.; Broder, S.; Roth, J. S.;
Driscoll, J. S. Biochem. Pharmacol. 1987, 36, 2719; (c)
Marquez, V. E.; Tseng, C. K.-H.; Mitsuya, H.; Aoki, S.;
Kelly, J. A.; Ford, H., Jr.; Roth, J. S.; Broder, S.;
Johns, D. G.; Driscoll, J. S. J. Med. Chem. 1990, 33,
978.
2. Herdewijn, P.; Pauwels, R.; Baba, M.; Balzarini, J.; De
Clercq, E. J. Med. Chem. 1987, 30, 2131.
3. (a) Hitchcock, M. J. M.; Woods, K.; De Boeck, H.; Ho,
H.-T. Antiviral Chemistry and Chemotherapy 1990, 5,
319; (b) Marquez, V. E.; Tseng, C. K-H.; Misty, H.;
Okay, S.; Kelly, J. A.; Ford, H., Jr.; Roth, J. S.; Johns,
D. G.; Driscoll, J. S. J. Med. Chem. 1990, 33, 978.
4. (a) Shiragami, H.; Tanaka, Y.; Uchida, Y.; Iwagami,
H.; Izawa, K.; Yukawa, T. Nucleosides Nucleotides 1992,
11, 391; (b) Marquez, V. E.; Driscoll, J. S.; Wysocki, R.
J., Jr.; Siddiqui, M. A. US 5817799; (c) Siddiqui, M. A.;
Marquez, V. E.; Driscoll, J. S.; Barchi, J. J. Tetrahedron
Lett. 1994, 35, 3263; (d) Takamatsu, S.; Maruyama, T.;
Katayama, S.; Hirose, N.; Naito, M.; Izawa, K. Tetra-
hedron Lett. 2001, 42, 2325; (e) Siddiqui, M. A.;
18. To a solution of compound 6 (3.8 g, 10.2 mmol) in 30
mL of dichloromethane was added pyridine (1.8 mL,
22.3 mmol) followed by acetic anhydride (2.1 mL, 22.3
mmol). The reaction mixture was stirred for 3 days.
Standard work-up provided the crude acetate 7 (3.9 g)
as an oily product. 1H NMR (CDCl3): l 7.68–7.64 (m,
4H), 7.42–7.35 (m, 6H), 6.32 (d, J=9 Hz, 1H), 5.13 and
4.95 (ddt, 1H, J=55.88, 5.4, 1.2 Hz), 4.47–4.8 (m, 1H),
3.83–3.64, m, 2H), 2.49–2.1 (m, 2H), 2.05 (s, 3H), 1.05
(s, 9H). To a solution of compound 7 (1.02 g, 2.45
mmol) in dichloromethane at 0°C was added BiBr3 (50
mg) followed by TMSBr (1.3 mL). The solution was
stirred in ice bath until the absence of 7 was observed