G. Zhang et al. / Tetrahedron Letters 48 (2007) 3413–3416
3415
subsequent treatment with TBAF and DIBAL-H affor-
a,b-unsaturated lactone conveniently in large scale. In
addition, starting from this lactone, four stereoisomers
of 3-azido-2,3,6-trideoxy-L-hexoses, protected forms of
daunosamine, ristosamine, acosamine, and epi-daunos-
amine were successfully prepared. We have developed
a new effective divergent approach to 3-amino-2,3,6-tri-
deoxy sugars. Additional applications of these azido
sugars in the preparation of new types of anthracyclines
are currently undergoing in our laboratory.
ded azido sugar 714 in 45% overall yield from 14.
In order to synthesize azido sugar 4, lactone 3 was firstly
converted to another lactone 1014 by reaction with
HOAc in the presence of DEAD and triphenylphos-
phine as shown in Scheme 2. When the conversion of
10 to epoxide 11 was performed according to the proce-
dure for preparation of epoxide 13, we found it did not
work well. Fortunately, the reagent PhCO3H worked
well for the conversion in the benzene at 0 °C. Treat-
ment of epoxide 11 by following the procedure for prep-
aration of 14 from 13 afforded an azido lactone which
was readily converted to azidosugar 4 after subsequent
treatment with anhydrous K2CO3 and DIBAL-H in
30% yield (overall yield of three reaction steps).
Acknowledgments
This work was supported by the National Natural
Science Foundation of China (20672031) and a fund
from the Program for New Century Excellent Talents
in University of Henan Province to G. Zhang.
When lactone 3 was subjected to the epoxidation condi-
tions (NaClO/pyridine), epoxide 8 was isolated in 39%
yield. Acetylation of epoxide 8 afforded another epoxide
9. Compound 9 was converted azidosugar 514 by follow-
ing the procedures for the preparation of azidosugar 4
from epoxide 11 in 35% overall yield for the four reac-
tion steps.
References and notes
1. (a) Arcamone, F.; Franceschi, G.; Minghetti, A.; Penco,
S.; Redaelli, S. J. Med. Chem. 1974, 17, 335–337; (b)
Arcamone, F.; Franceschi, G.; Orezzi, P.; Cassinelli, G.;
Barbieri, W.; Mondelli, R. J. Am. Chem. Soc. 1964, 86,
5334–5335; (c) Arcamone, F.; Cassinelli, G.; Orezzi, P.;
Franceschi, G.; Mondelli, R. J. Am. Chem. Soc. 1964, 86,
5335–5336.
2. Arcamone, F.; Bernardi, L.; Giardino, P.; Patelli, B.; Di
Marco, A.; Casazza, A. M.; Pratesi, G.; Reggiani, P.
Cancer Treat. Rep. 1976, 60, 829–834.
3. Coukell, A. J.; Faulds, D. Drugs 1997, 53, 453–482.
4. Oki, T.; Shibamoto, N.; Matsuzawa, Y.; Ogasawara, T.;
Yoshimoto, A.; Kitamura, I.; Inui, T.; Naganawa, H.;
Takeuchi, T.; Umezawa, H. J. Antibiot. 1977, 30, 683–
687.
5. Oki, T. Jpn. J. Antibiot 1977, 30, 70–84.
6. Oki, T.; Matsuzawa, Y.; Yoshimoto, A.; Numata, K.;
Kitamura, I. J. Antibiot. 1975, 28, 830–834.
7. Umezawa, H.; Takahashi, Y.; Kinoshita, M.; Naganawa,
H.; Masuda, T.; Ishizuka, M.; Tatsuta, K.; Takeuchi, T. J.
Antibiot. 1979, 32, 1082–1084.
8. Israel, M.; Modest, E. J.; Frei, E. Cancer Res. 1975, 35,
1365–1368.
9. Arcamone, F.; Penco, S.; Vigevani, A.; Redaelli, S.;
Franchi, G.; Di Marco, A.; Casazza, A. M.; Dasdia, T.;
Formelli, F.; Necco, A.; Soranzo, C. J. Med. Chem. 1975,
18, 703–707.
10. (a) Renneberg, B.; Li, Y.-M.; Laatsch, H.; Fiebig, H.-H.
Carbohydr. Res. 2000, 329, 861–872; (b) Herczegh, P.;
Zsely, M.; Kovacs, I.; Batta, G.; Sztaricskai, F. J.
Tetrahedron Lett. 1990, 31, 1195–1198; (c) Gurjar, M.
K.; Pawar, S. M. Tetrahedron Lett. 1987, 28, 1327–1328.
11. Wovkulich, P. M.; Uskokovic, M. R. J. Am. Chem. Soc.
1981, 103, 3956–3958.
Recently we reported a daunorubicin analogue 30-azido-
30-deamino daunorubicin (18) that shows significant
anticancer activity against drug-resistant cancers in cell
cultures (in vitro) and in a xenograft model in vivo,
increases animal survival rate, and decreases general
toxicity in the animal model.13b It was synthesized by
treatment of daunorubicin with a TfN3 solution in
70% yield. In this Letter we present an alternative
synthetic method of the daunorubicin analogue as an
example of the glycosylation of anthracyclinones with
azidosugars (Scheme 3). Acetyl group was used for pro-
tecting the hydroxyl groups present in the azidosugar
molecule, because they were cleavable under 0.1 M
NaOH in THF at 0 °C, which allowed the acid and
strong base-sensitive aglycon moiety in the anthra-
cyclines not to be affected in the final deprotection pro-
cedures. As shown in Scheme 3, after treatment with
phenylthiol in the presence of BF3ÆEt2O at 0 °C for
3 h, the desired sugar donor 16 was obtained in good
yield. The thiolglycoside was obtained as a mixture of
a- and b-isomers. Since both isomers are able to be used
for the glycosylation to produce the desired a-linked
daunorubicin derivatives, separation was not necessary.
With daunorubicinone 17 and the sugar donor in hand,
the glycosylation was performed subsequently. The mix-
ture of aglycon 17 and sugar donor 16, in the presence of
˚
TTBP (2,4,6-tri-tert-butylpyrimidine) and 4 A molecular
sieves, was treated with AgPF6 at 0 °C for 4 h to give
12. Ginesta, X.; Pasto, M.; Pericas, M. A.; Riera, A. Org.
Lett. 2003, 5, 3001–3004.
1
a unseparated mixture. The H NMR data of this mix-
13. (a) Zhang, G.; Fang, L.; Zhu, L.; Zhong, Y.; Wang, P. G.;
Sun, D. J. Med. Chem. 2006, 49, 1792–1799; (b) Fang, L.;
Zhang, G.; Li, C.; Zheng, X.; Zhu, L.; Xiao, J. J.; Szakacs,
G.; Nadas, J.; Chan, K. K.; Wang, P. G.; Sun, D. J. Med.
Chem. 2006, 49, 932–941.
ture indicated that the desired a-linkage was formed
predominantly (a:b ꢁ 5:1). Treatment of the mixture
with 0.1 M NaOH in THF gave the glycosylated prod-
uct 18 in 50% overall yield for the two reaction steps
after purification through a silica gel column using
MeOH/CH2Cl2 (1:100–50).
14. Spectroscopic data: Compound 2 1H NMR (400 MHz,
CDCl3) d 6.75 (dd, J = 9.9, 3.2 Hz, 1H), 6.07 (dd, J = 9.9,
1.5 Hz, 1H), 5.58–5.53 (m, 1H), 5.24 (dd, J = 8.9, 2.2 Hz,
1H), 2.10 (s, 3H), 1.39 (d, J = 6.6 Hz, 3H); 13C NMR
(100 MHz, CDCl3) d 162.3, 143.1, 123.0, 76.6, 67.9, 21.0,
In summary, by utilizing the BF3ÆOEt2-induced per-
oxidation of rhamnal, we were able to generate the