A. Choudhury et al. / Tetrahedron Letters 46 (2005) 8099–8102
8101
Table 1. Effect of base
References and notes
Base
% Conversiona
Base
% Conversiona
1. (a) Ferrier, R. J.; Prasad, N. J. Chem. Soc. 1969, 570; (b)
Ferrier, R. J. Adv. Carbohydr. Chem. 1965, 20, 67; (c)
Ferrier, R. J. Adv. Carbohydr. Chem. 1969, 24, 199.
2. (a) Tam, S. Y.-K.; Fraser-Reid, B. Can J. Chem. 1977, 55,
3996; (b) Okabe, M.; Sun, R.-C. Tetrahedron Lett. 1989,
30, 2203.
Pempidine
DIPEA
NaH
65–70
25
50
TBA
DBU
TEA
50
60
25–30
a Reactions stops after the conversion shown, remainder of the glycal
aromatizes.
3. Ireland, R. E.; Wilcox, C. S.; Thaisrivong, S. J. Org.
Chem. 1978, 43, 786.
NH2
4. Haga, M.; Ness, R. K. J. Org. Chem. 1965, 30, 158.
5. Ferrier, R. J. J. Chem. Soc. 1964, 5443; For a discussion
on different types of acid catalyst used in Ferrier reaction
see: Wieczorek, E.; Thiem, J. J. Carbohydr. Chem. 1998,
17, 785, and references cited therein.
F
N
NH2
PO
O
O
N
F
a
N
b
1
+
5
6. Taniguchi, M.; Koga, K.; Yamada, S. Tetrahedron 1974,
30, 3547.
O
N
H
7. (a) Shi, J.; McAtee, J.; Wirtz, S. S.; Tharnish, P.;
Juodawlkis, A.; Liotta, D. C.; Schinazi, R. F. J. Med.
Chem. 1999, 42, 859; (b) Schinazi, R. F. et al. Antimicrob.
Agent. Chemother. 2002, 46, 1394.
8. Holzapfel, C. W.; Koekemoer, J. M.; Verdoorn, G. H.
S.Afr. Tydskr. Chem. 1986, 39, 151.
7
6
Scheme 2. Reagents and conditions: (a) DBU, NMP, 3 mol % Pd(0),
33 °C, 2 d, 76–80% conversion, 50% isolated yield; (b) 7 mol %
NaOMe/MeOH, 18 h, 82%.
9. (a) Kassou, M.; Castillon, S. Tetrahedron Lett. 1994, 35,
5513; (b) Larsen, E.; Jorgensen, P. T.; Sofan, A. M.;
Pedersen, E. B. Synthesis 1994, 1037; (c) Abramski, W.;
Chmielewski, M. J. Carbohydr. Chem. 1994, 13, 125; (d)
Walker, J. A.; Chen, J. J.; Wise, D. S.; Townsend, L. B. J.
Org. Chem. 1996, 61, 2219.
10. Diaz, R. R.; Melgarejo, C. R.; Cubero, I. I.; Lopez-
Espinosa, M. T. P. Carbohydr. Res. 1997, 300, 375.
11. Robles, R.; Rodriguez, C.; Izquierdo, I.; Plaza, M. T.;
Mota, A. Tetrahedron: Asymmetry 1997, 8, 2959.
12. (a) Garegg, P. J.; Samuelson, B. Synth. Commun. 1979,
469; (b) Kassou, M.; Castelino, S. Tetrahedron. Lett. 1994,
5513.
highest conversion and cleaner reaction profile. But for
high cost of pempidine, we preferred to use DBU as
the base of choice. Catalyst loading was optimized with
DBU as the base and acetonitrile as the solvent. Among
the variations tried, that is, 1%, 3%, 10%, 3 mol % was
found to be the optimal. Optimization of the solvent
(NMP, DMF, toluene, DCM, acetonitrile) with DBU
as the base with 3 mol % of Pd(Ph3P)4 as the catalyst
showed NMP as the solvent of choice.
A Ferrier type allylic coupling of the unprotected base,
fluorocytocine (6) with glycal 5 in the presence of
Pd(Ph3P)4 (tetrakis-triphenyl phosphine palladium(0))
catalyst20 provided the 50-anisoyl-DD4FC in good iso-
lated yield (Scheme 2).
13. Use of p-nitrobenzoyl groupas the protecting groupled to
spontaneous elimination during the glycal formation step
leading to the aromatized product. Acetyl protection led
to aromatization during the glycosylation reaction with
fluorocytocine.
14. No aromatized product was observed. The rest of the
impurity seemed to come from the resin. It was found that
10 upon concentration using 2:1 hexanes/toluene becomes
a solid but generate more impurity. The preferred way to
It is worth noting that sequence of addition of reagents
is critical for success of these reactions.20,21 The isolation
of the nucleoside was extremely simple and required no
chromatography. The reaction mixture was poured into
water and the mixture was extracted with ethylacetate.
Solvent exchange with toluene generated 7, which on
subsequent deprotection of 50-anisoyl groupprovided
the DD4FC. The product (1) has identical HPLC reten-
tion times, 19F, 1H, and 13C NMR spectrum with
authentic DD4FC (13).22
˚
save it is as a solution in acetonitrile stored over 4 A
molecular sieves free of moisture and acids. This way of
preservation retains the stability of the glycal at least over
2–3 weeks without degradation.
15. (a) Bolitt, V.; Chaguir, B.; Sinou, D. Tetrahedron Lett.
1992, 33, 2481; (b) Comely, A. C.; Eelkema, R.; Minn-
aard, A. J.; Feringa, B. L. J. Am. Chem. Soc. 2003, 125,
8714; (c) Babu, R. S.; OÕDoherty, G. A. J. Am. Chem. Soc.
2003, 125, 12406; (d) Kim, H.; Men, H.; Lee, C. J. Am.
Chem. Soc. 2004, 126, 1336.
16. (a) RajanBabu, T. V. J. Org. Chem. 1985, 50, 3642; (b)
Coleman, R. S.; Madaras, M. J. Org. Chem. 1998, 63,
5700.
17. Qutten, R. A.; Daves, G. D. J. Org. Chem. 1989, 54, 29.
18. Trost, B. M.; Shi, Z. J. Am. Chem. Soc. 1996, 118, 3037.
19. Wolfe, J. P.; Wagaw, S.; Marcoux, J. F.; Buchwald, S.
Acct. Chem. Res. 1998, 31, 805–818.
In conclusion, we have demonstrated that the aromati-
zation prone glycal can be successfully used in a Ferrier
rearrangement type products generation using Pd(0) as
the catalyst. The high regio and stereoselective product
formation leads to a concise synthesis of DD4FC, a
nucleoside reverse transcriptase inhibitor. We have also
demonstrated that this coupling reaction can be
extended to other nucleophiles.
20. Control experiment via fluorine and proton NMR in
tetrahydrofuran-d8 showed that the glycal 10 aromatizes
to furan derivative (50% in 0.5 h) in presence of tetrakis
triphenyl phosphine Palladium(0) and in the absence of an
added nucleophile.
Acknowledgement
We would like to thank Professor Barry M. Trost, Dr.
William F. Nugent, and Dr. Joseph M. Fortunak for
helpful discussions.
21. Addition of catalyst to the glycal at room temperature
causes aromatization, but when catalyst is added to a