the Kishi and Schmidt and Jiminez-Barbero groups, which
focused on NOE data and modeling results. There is partial
but not complete agreement with regard to the similarities
and differences in the conformation of ground-state and of
binding conformations.3-5 Nonetheless, the Ki values for O-
and C-lactose for the competitive inhibition of â-galactosi-
dase-catalyzed cleavage of p-nitrophenyl galactose are 1 and
3 µM, respectively, which suggest a close similarity if not
perfect identity of the two materials in their binding to the
enzyme. Three other close comparisons include binding of
a blood group trisaccharide to a leguminous lectin,6 oligo-
â-1,6-galactosides to three monoclonal immunoglobulins,7
and a trimannose analogue containing one C-linkage to
concanavalin A.8 In the first two of these comparisons, the
affinities of the O-glycosides and their exact C-analogues
were essentially identical. In the last report, the binding
decreased by 66-fold (from 3 µM for the O-trimannose to
198 µM for the mono-C-analog). An early comparison is
that between the antitumor activity of daunomycin and its
nonexact C-analogue, with ED50 values vs L1210 cells of
0.013 and 4 µM, respectively.9 Recently we had reported a
comparison between an antiproliferative 2-deoxyglucosyl
glycerolipid and its exact C-analogue in which the C-
glycoside showed a severalfold weaker activity.10 We now
wish to describe an example in which the O- and C-
glycerolipids of glucosamine display very similar micromolar
antiproliferative activity against nine tumor cell lines.
Taylor’s.13 After the rather guarded outlook for the synthesis
of C-glycosides of 2-amino sugars that was expressed in
1996,14 several useful approaches have been reported.15
However, we believed that our method offers both simplicity
and certain â-anomeric selectivity.
Previously, we had synthesized 2-deoxy C-glycoside 1c
by introducing a methyl ether into its thioglycoside precursor
via O-methylation of the side chain hydroxyl immediately
prior to the RB rearrangement. The corresponding O-
methylation step is not clean in the 2-acetaminoglucose series
because N-methylation also takes place. Therefore, the
sequence was modified by installing the O-methyl group
before the thioglycoside was prepared. The synthesis of the
lipid (S)-4-O-hexadecyl-3-O-methyl-1-iodobutane (6) was
easily accomplished starting from (S)-(-)-1,2,4-butanetriol
2 (Scheme 1). This procedure is based on selective protection
Scheme 1a
a Reagents and conditions: (a) ref 10; (b) (1) 80% AcOH, reflux,
81%, (2) TBDMSCl, CH2Cl2, imidazole, 87%; (c) (1) NaH, MeI,
THF, 92%, (2) Bu4NF, THF, 83%; (d) Ph3P, I2, imidazole, toluene,
reflux, 70%.
Our plan was to compare glucosamine derivatives 1a and
1b since we had shown earlier that O-glycoside 1a had
micromolar antiproliferative activity in assays against several
tumor cell lines.11 This lead compound had been prepared
via a zinc chloride catalyzed version of the Koenigs-Knorr
reaction of 1-chlorotetra-O-acetylglucosamine (the intermedi-
ate in the conversion of 7 to 8) and the appropriate modified
glycerol. For the preparation of 1b, we chose to test the
Ramberg-Ba¨cklund (RB)12 method for the synthesis of
C-glycosides, under development by both our group and
of 2 followed by O-alkylation.10 Deprotection of 3 using 80%
acetic acid at reflux, followed by selective silylation of the
primary alcohol afforded silyl ether 4. O-Methylation fol-
lowed by deprotection of silyl group gave primary alcohol
5. 4-O-Hexadecyl-3-O-methyl-1-iodobutane (6) was prepared
from 5 and I2/Ph3P at reflux in toluene.
N-Acetyl-3,4,6-tri-O-acetyl-1-glucosamine thioacetate (8)
was synthesized from commercial N-acetyl-D-glucosamine
(6) Wei, A.; Boy, K. M.; Kishi, Y. J. Am. Chem. Soc. 1995, 117, 9432-
9436.
(13) Belica, P. A.; Franck, R. W. Tetrahedron Lett. 1998, 39, 8225-
8228. (b) Ref 10. (c) Griffin, F. K.; Murphy, P. V.; Patterson, D. E.; Taylor,
R. J. K. Tetrahedron Lett. 1998, 39, 8179-8182. (d) Alcaraz, M.-L.; Griffin,
F. K.; Patterson, D. E.; Taylor, R. J. K. Tetrahedron Lett. 1998, 39, 8183-
8186. (e) Taylor, R. J. K.; Griffin, F. K.; Paterson, D. E. Angew. Chem.,
Int. Ed. 1999, 38, 2939-2942. (f) Campbell, A. D.; Paterson, D. E.;
Raynham, T. M.; Taylor, R. J. K. J. Chem. Soc., Chem. Commun. 1999,
1599-1600. (g) Falconer, R. A.; Toth, I. 20th International Carbohydrate
Symposium, Hamburg, Aug. 28-Sept. 2, 2000, Poster B-348.
(14) Roe, B. A.; Boojamra, C. G.; Griggs, J. L.; Bertozzi, C. R. J. Org.
Chem. 1996, 61, 6442-6445. “Unfortunately, C-glycosyl derivatives of
2-amino sugars are among the most difficult to prepare as a result of the
incompatibility of neighboring nitrogen-based functional groups (i.e., amides,
carbamates, and azides) with common C-glycosylation strategies.”
(15) Free-radical methods: (a) ref 14. (b) Gaurat, O.; Xie, J.; Valery,
J.-M. Tetrahedron Lett. 2000, 41, 1187-1189. (c) Junker, H.-D.; Phung,
N.; Fessner, W.-D. Tetrahedron Lett. 1999, 40, 7063-7066. (d) Cui, J.;
Horton, D. Carbohydr. Res. 1998, 309, 319-330. Organosamarium
methods: (e) Andersen, L.; Munch, L.; Beau, J.-M.; Skrydstrup, T. Synlett
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Res. 1998, 308, 191-193.
(8) Tsuruta, O.; Yuasa, H.; Kurono, S.; Hashimoto, H. Bioorg. Med.
Chem. Lett. 1999, 9, 807-810.
(9) Acton, E. M.; Ryan, K. J.; Tracy, M.; Arora, S. K. Tetrahedron Lett.
1986, 27, 4245-4248. (b) Welch, S. C.; Levine, J. A.; Arimilli, M. N.
Synth. Commun. 1993, 23, 131-134.
(10) Yang, G.; Franck, R. W.; Byun, H.-S.; Bittman, R.; Samadder, P.;
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(11) Erukulla, R. K.; Zhou, X.; Samadder, P.; Arthur, G.; Bittman, R. J.
Med. Chem. 1996, 39, 1545-1548.
(12) Paquette, L. A. Org. React. 1977, 25, 1-71. (b) Guziec, F. S., Jr.;
San Filippo, L. J. Tetrahedron 1988, 44, 6241-6285. (c) Oae, S.; Uchida,
Y. (Chapter 12); Braverman, S. (Chapter 13) In The Chemistry of Sulfones
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