C O M M U N I C A T I O N S
macrocyclization,18b furnishing the cyclic 24 in 50-60% yield.
At this stage, the two C3′ epimers (24a and 24b, formed without
a preference) were able to be separated readily by chromatog-
raphy on silica gel. Finally, the 16 Bn groups were taken off
cleanly by hydrogenolysis over Pd(OH)2, leading to the target
Lobatoside E (1) and its epimer 25, respectively (∼80%). The
analytical data of 1 are in good agreement with those reported
for the natural product,2,20 while the NMR spectra of its epimer
25 show minor differences between signals from the atoms
proximal to the epimeric C3′.
Scheme 2
In summary, Lobatoside E (1), a complex cyclic bisdesmoside
showing potent antitumor activities, has been synthesized for
the first time. This highly modular synthesis requires a total of
73 steps starting with cheap materials, with the longest linear
sequence of 31 steps and in 1.2% overall yield.
Acknowledgment. This work was support by the NSFC
(20621062 and 20432020) and the CAS (KGCX2-SW-213,
-209).
Supporting Information Available: Experimental details, char-
1
acterization data, and H NMR spectra for new compounds. This
material is available free of charge via the Internet at http://
pubs.acs.org.
References
(1) (a) Kasai, R.; Miyakoshi, M.; Matsumoto, K.; Nie, R. L.; Zhou, J.; Morita,
T.; Tanaka, O. Chem. Pharm. Bull. 1986, 34, 3974. (b) Kong, F. H.; Zhu,
D. Y.; Xu, R. S.; Fu, Z. C.; Zhou, L. Y.; Iwashita, T.; Komura, H.
Tetrahedron Lett. 1986, 27, 5765. (c) Kasai, R.; Miyakoshi, M.; Nie, R. L.;
Zhou, J.; Matsumoto, K.; Morita, T.; Nishi, M.; Miyahara, K.; Tanaka, O.
Phytochemistry 1988, 27, 1439. (d) Kong, F. H.; Zhu, D. Y.; Xu, R. S.;
Fu, Z. C. Acta Chim. Sin. 1988, 46, 409. (e) Tang, H. F.; Yi, Y. H.; Zhang,
S. Y.; Sun, P.; Li, L.; Zhou, D. Z. Chin. Chem. Lett. 2005, 16, 479.
(2) (a) Fujioka, T.; Iwamoto, M.; Iwase, Y.; Hachiyama, S.; Okabe, H.;
Yamauchi, T.; Mihashi, K. Chem. Pharm. Bull. 1989, 37, 1770. (b) Fujioka,
T.; Iwamoto, M.; Iwase, Y.; Hachiyama, S.; Okabe, H.; Yamauchi, T.;
Mihashi, K. Chem. Pharm. Bull. 1989, 37, 2355.
(3) Fujioka, T.; Kashiwada, Y.; Okabe, H.; Mihashi, K.; Lee, K. H. Bioorg.
Med. Chem. Lett. 1996, 6, 2807.
(4) (a) Cheng, G.; Zhang, Y.; Zhang, X.; Tang, H. F.; Cao, W. D.; Gao, D. K.;
Wang, X. L. Bioorg. Med. Chem. Lett. 2006, 16, 4575. (b) Wang, F.; Ma,
R.; Yu, L. Cancer Chemother. Pharmacol. 2006, 57, 389.
(5) For the synthesis of the building blocks 3-7, see Supporting Information.
(6) (a) Kim, Y. J.; Wang, P.; Navarro-Villalobos, M.; Rohde, B. D.; Derryberry,
J.; Gin, D. Y. J. Am. Chem. Soc. 2005, 127, 3256. (b) Sun, J.; Han, X.;
Yu, B. Org. Lett. 2005, 7, 1935.
(7) (a) Bliard, C.; Massiot, G.; Nazabadioko, S. Tetrahedron Lett. 1994, 35,
6107. (b) Peng, W.; Han, X.; Yu, B. Synthesis 2004, 10, 1641.
(8) Yu, B.; Li, B.; Xing, G.; Hui, Y. J. Comb. Chem. 2001, 3, 404.
(9) Wen, X.; Zhang, P.; Liu, J.; Zhang, L.; Wu, X.; Ni, P.; Sun, H. Bioorg.
Med. Chem. Lett. 2006, 16, 722.
(10) (a) Baldwin, J. E.; Jones, R. H.; Najera, C.; Yus, M. Tetrahedron 1985,
41, 699. (b) Carr, K.; Saxton, H. M.; Sutherland, J. K. J. Chem. Soc., Perkin
Trans. 1 1988, 1599. (c) Peakman, T. M.; Lo ten Haven, H.; Rullkotter, J.
Tetrahedron 1991, 47, 3779.
(11) (a) Bore, L.; Honda, T.; Gribble, G. W. J. Org. Chem. 2000, 65, 6278. (b)
Garcia-Granados, A.; Lopez, P. E.; Melguizo, E.; Parra, A.; Simeo, Y. J.
Org. Chem. 2007, 72, 3500.
(12) (a) Rubottom, G. M.; Vazquez, M. A.; Pelegrina, D. R. Tetrahedron Lett.
1974, 15, 4319. (b) Hassner, A.; Reuss, R. H.; Pinnick, H. W. J. Org.
Chem. 1975, 40, 3427.
(13) Voigt, B.; Porzel, A.; Adam, G.; Golsch, D.; Adam, W.; Wagner, C.;
Merzweiler, K. Collect. Czech. Chem. Commun. 2002, 67, 91.
(14) Klinot, J.; Sejbal, J.; Vystrcil, A. Collect. Czech. Chem. Commun. 1989,
54, 400.
(15) Lee, S.-S.; Chen, W.-C.; Huang, C.-F.; Su, Y. J. Nat. Prod. 1998, 61, 1343.
(16) Lefeber, D. J.; Kamerling, J. P.; Vliegenthart, J. F. G. Org. Lett. 2000, 2,
701.
(17) Baptistella, L. H. B.; dos Santos, J. F.; Ballabio, K. C.; Marsaioli, A. J.
Synthesis 1989, 436.
-20 °C provided the ꢀ-glucoside 16 (96%). The hindrance of
the 2-O-position in the glucose unit (in 16) raised problems for
further elaboration; nevertheless, selective removal of the CA
group (vs the Ac group) was finally achieved with DABCO to
afford 17 (100%);16 glycosylation of the resulting -OH with
the galactosyl imidate 55 (TMSOTf, -20 °C) proceeded
sluggishly; addition in portions of 5 equiv of the donor 5 led to
the ꢀ-galactoside 18 in 65% yield. Glycosylation at elevated
temperatures (e.g., rt) led to anomerization of the ester arabinosyl
linkage. Selective removal of the Ac group (vs the Bz group in
18) was realized with DBU to give 19 (97%),17 which was
glycosylated with thiodisaccharide 65 (NIS, TMSOTf) to afford
stereoselectively the R-rhamnosyl-linked pentasaccharide 20
(81%). The Bz group in the galactose unit was then replaced
by a Bn group, without optimization, to give 21 (51%, 19%
recovered).
The availability of the pentasaccharide 21 set a final stage
for the elaboration of the target molecule (1). Thus, the TBDPS
group was removed cleanly with TBAF (98%), and the resulting
primary hydroxyl group was condensed with acid 75 under the
Yamaguchi conditions18 to provide 22 (96%), where protection
of the tertiary hydroxyl group of the glutarate was found to be
mandatory. Removal of the two PMB groups was effected with
CF3COOH to give 23 (95%).19 The two oligosaccharide residues
in 23 (at 0.001 M) were then bridged by the Yamaguchi
(18) (a) Inanaga, J.; Hirata, K.; Saeki, H.; Kattsuki, T.; Yamaguchi, M. Bull.
Chem. Soc. Jpn. 1979, 52, 1989. (b) Thijs, L.; Egenberger, D. M.;
Zwanenburg, B. Tetrahedron Lett. 1989, 30, 2153.
(19) De Medeiros, E. F.; Herbert, J. M.; Taylor, R. J. K. J. Chem. Soc., Perkin
Trans. 1 1991, 2725.
(20) The S configuration at C3′ has been determined in two congeners of
Lobatoside E.1a,c
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