Scheme 1
compromised due to use of an ether-type protecting group.
Treatment of 33 with boron trifluoride etherate (1.5 equiv)
in the presence of dibenzyl-sugar 44 (>90% â) in acetonitrile
at -10 °C led to the formation of a crystalline slurry within
10 min (Scheme 1). HPLC analysis of the mixture after 20
min revealed that the reaction was essentially complete
(<1.5% of 3) and showed the presence of the desired,
coupled product 2â along with 2R in a ratio of 2.4:1.
Surprisingly, analysis of the solid revealed the presence of
2â:2R in a ratio of 95:5. After the crystallization was
complete (5 h), pyridine was added to quench the Lewis acid.
Extractive workup afforded the coupled product after crystal-
lization from acetonitrile. The isolated solid 2â contained
only a trace of 2R as determined by HPLC analysis.5,6
Apparently, once the crystallization commences, the equi-
librium is driven toward 2â, thus leading to a crystallization-
In particular, examination of literature precedent and our
earlier studies on the synthesis of etoposide phosphate
established that the hydrolytic conditions, required for
removal of the C-1 oxygen protecting group of 4, led to the
formation of an anomeric mixture. Altough 4 could be
converted primarily to the â-isomer by heating below its
melting point, we found that 4â underwent partial anomer-
ization under the reaction conditions (Lewis acid) required
for coupling of the sugar to the aglycone.
(2) (a) von Kuhn, M.; von Wartburg, A. HelV. Chim. Acta 1968, 51,
1631. (b) Kuhn, M.; von Wartburg, A. HelV. Chim. Acta 1969, 52, 948. (c)
Wang, Z.; Ma, W.; Zhang, C. U.S. Pat. 5,206,350, 1993. (d) Kurabayash,
K.; Kinoshita, H.; Saito, H.; Takahashi, T. Eur. Pat. 111058-A1, 1984. (e)
Saito, H.; Nishimura, Y.; Kondo, S.; Umezawa, H. Chem. Lett. 1987, 799.
(f) Fujii, T.; Chikui, Y. U.S. Pat. 4,757,138, 1988. (g) Kolar, C.;
Moldenhauer, H.; Kneissl, G. J. Carbohydr. Chem. 1990, 9, 571. (h) Sterling,
J.; Nudelman, A.; Herzig, J.; Keinan, E.; Weiner, B. Z. U.S. Pat 4,900,-
814, 1990. (i) Ohnuma, T.; Hoshi, C. U.S. 4,997,931, 1991. (allopyranose,
not etoposide) (j) Kolar, C. Eur. Pat. 394907-A1, 1990. (k) Robin, J.-P.;
Houlbert, N.; Lenain, V. Eur. Pat. 435709-A1, 1991. (l) Robin, J.-P.; Lenain,
V. Eur. Pat. 445021-A2 1991. (m) Hashimoto, S.; Honda, T.; Ikegami, S.
Tetrahedron Lett. 1991, 32, 1653. (n) Nudelman, A.; Herzig, J.; Keinan,
E.; Weiner, B. Z.; Sterling, J. Eur. Pat. 226,202, 1987. (o) Allevi, P.;
Anastasia, M.; Ciuffreda, P.; Sanvito, A. M.; Macdonald, P. Tetrahedron
Lett. 1992, 33, 4831. (p) Miyazawa, Y.; Sato, H.; Yoshikawa, H.; Kouichi,
O.; Noriko, T. Eur. Pat. 0567089-A1. (q) Vogel, C. U.S. Pat. 5,463,040.
(r) Allevi, P.; Anastasia, M.; Bigatti, E.; Macdonald, P. WO 9302094 1993.
(s) Allevi, P.; Anastasia, M.; Ciuffreda, P.; Bigatti, E.; Macdonald, P. J.
Org. Chem. 1993, 58, 4175. (t) Vogel, K.; Sterling, J.; Herzig, Y.; Nudelman,
A. Terahedron 1996, 52, 3049. (u) Fusauchi, Y. M.; Yoshikawa, H. F. Eur.
Pat. Appl. 0778282-A1. (v) Zhao, Y.-H.; Yang, F.-Y.; Gu, K.; Li, R.-Y.;
Wang, J. K. Stud. Plant Sci. 1999, 6 (Advances in Plant Glycosides,
Chemistry and Biology), 330.
(3) Stehelin, H. F.; Hansen, R. B.; Willumsen, A. M.; Jorslov-Lauritsen,
N.; Ebbesen, P.; Nielsen, P. E.; Buchardt, O. Acta Chem. Scand. 1993, 47,
1190.
(4) Silverberg, L. J.; Dillon, J. L.; Vemishetti, P.; Sleezer, P. D.;
Discordia, R. P.; Hartung, K.; Gao, Q. Org. Process Res. DeV. 2000, 4, 34.
(5) Formation of the R-isomer with respect to the O-C bond of the sugar
and lignan nucleus in coupled product 2 is not observed presumably due to
steric hindrance of the R-face by the pendant aryl ring system.
(6) Prior to addition of pyridine, the crystalline slurry could be filtered
cold to afford 2â:2R in a ratio of approximately 95:5 in a yield of 78%. In
practice it was more suitable to quench the reaction with pyridine and
perform an extractive workup to afford a more stable crystalline form of
2â. One batch which was directly isolated was shown to be unstable,
presumably due to the presence of trace amounts of BF3 that were occluded
in the crystals. Also, by quenching and workup, 2â can be isolated from
acetonitrile at higher temperature (0 °C), allowing for a nearly complete
purge of the 2R isomer.
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Org. Lett., Vol. 2, No. 21, 2000