9802
J. Am. Chem. Soc. 1996, 118, 9802-9803
The Synthesis of C-Trisaccharides Exploiting the
Stereochemical Diversity of a Central Sugar
Daniel P. Sutherlin and Robert W. Armstrong*
Department of Chemistry and Biochemistry
UniVersity of California, Los Angeles, California 90095
ReceiVed March 7, 1996
The interaction between cell surface carbohydrates and their
protein receptors1 is implicated in viral2 and bacterial3 adhesion,
metastasis,4 and the recruitment of leukocytes.5 Carbohydrate
mimics represent a class of compounds which can be used to
study these cellular interactions and may represent leads for
drug discovery.6 In particular, C-glycosides are useful candi-
dates due to their resistance to glycosidases, greatly enhancing
their stability in biological fluids.7 In reference to the generation
of di- and trisaccharide analogs, Kishi has shown that in specific
models, C-glycosides are similar in both solution conformation
and biological activity to their O-glycosidic counterparts and
that hydroxyl deletion can alter the overall conformation and
flexibility of the C-saccharide.8 Presently, we are developing
substrates to examine these interactions at the molecular level
via de noVo synthesis of pyranyl derivatives within the context
of C-disaccharides9 and alternatively with the combinatorial
synthesis of C-glycopeptide ligands on solid support.10 In this
paper, we develop a general strategy for the synthesis of
C-trisaccharides11 with increasing levels of divergence through-
out the later stages of the route. Using this approach, we have
accomplished the synthesis of C-trisaccharides based on the H
type I blood group determinant 1 (Figure 1), implicated in
adhesion involving the pathogenic bacteria Helicobacter pylori.3b
Our synthetic strategy is based on the C-trisaccharide 2, a
mimic of blood group determinant 1, and represents a practical
method to rapidly sort novel trisaccharides via biological
evaluation of diastereomeric mixtures. The absolute structure
of a compound of interest can be determined via a recursive
stereochemical deconvolution of an active pool of diastereomeric
mixtures through further elaboration of archived intermediates
and subsequent retesting.12 Expanding on the concepts of our
previous work with 1,6 C-disaccharides,9 we used two fixed
pendant sugars at each terminus of the trisaccharide and created
de noVo the central core hexose in 2. Strategically, the pendent
sugar’s identity and connectivity could be easily changed,
Figure 1. Retrosynthetic analysis to diverse analogs of the H-type I
blood group.
Chart 1
making this approach general for any trisaccharide of interest
with a C-1 and C-2 linkage, a common motif. Permutational
alterations of the central hexose should have the most effect on
the overall three-dimensional conformation of the trisaccharide.
Retrosynthetic analysis of 2 affords the complex “C-disaccha-
ride” 3 that can be modified by the addition of a variety of
nucleophiles and then converted synthetically to 2 via an
intramolecular cyclization. Synthesis of 3 required an organo-
metallic coupling of C-hexose 4 and aldehyde 5, both derived
from natural sugar precursors. This strategy has thus far yielded
the six trisaccharides 6-11 through a rapid, convergent approach
that can be applied to a variety of cell-surface sugars. Both
the central D- and L-sugars are synthesized with no extra
synthetic effort, providing an interesting permutation that would
otherwise be financially prohibitive if natural sugar precursors
were used as starting materials.
(1) (a) Varki, A. Glycobiology 1993, 3, 97-130. (b) Feizi, T. Curr. Opin.
Struct. Bio. 1993, 3, 701. (c) Varki, A. Proc. Natl. Acad. Sci. U.S.A. 1994,
91, 7390.
(2) (a) Paulson, J. C. The Receptors; Academic: New York, 1985; Vol.
2. (b) Wharton, S. A.; Weis, W.; Skehel, J. J.; Wiley, D. C. The Influenza
Virus; Plenum: New York, 1989.
(3) (a) Gyler, M.; Rose, D.; Bundle, D. Science 1991, 253, 442. (b) Boren,
T.; Falk, P.; Roth, K. A.; Larson, G.; Normark, S. Science 1993, 262, 1892.
(4) (a) Phillips, M. L.; Nudelman, E.; Gaeta, F. C. A.; Perez, M.; Sinhal,
A. K.; Hakomori, S.; Paulson, J. C. Science 1990, 250, 1130. (b) Higashi,
H.; Hirabayashi, Y.; Fukui, Y.; Naiki, M.; Matsumoto, M.; Ueda, S.; Kato,
S. Cancer Res. 1985, 45, 3796-3802.
(5) (a) Butcher, E. C. Am. J. Path. 1990, 1, 3-11. (b) Walz, G.; Aruffo,
A.; Kolanus, W.; Polley, M. J.; Phillips, M. L.; Wagner, E.; Nudelman, E.;
Sinhal, A. K.; Hakomori, S.; Paulson, J. C. Proc. Natl. Acad. Sci. U.S.A.
1991, 88, 6224.
Vinyl bromide 4, generated in three steps from commercially
available fucose,13 was coupled to aldehyde 514 with CrCl2/
15
0.5% NiCl2 and blocked to obtain separable TBS ethers 12
(6) (a) Bertozzi, C. R. Chem. Biol. 1995, 11, 703-708. (b) Mulligan,
M. S.; Paulson, J. C.; De Frees, S.; Zheng, Z. L.; Lowe, J. B.; Ward, P. A.
Nature 1993, 364, 149-151.
and 13,16 2:1, respectively (Scheme 1). Diastereoselective
hydroboration/oxidation (9-BBN/H2O2)17 and subsequent oxida-
tion with Dess-Martin periodinane (DMP)18 gave aldehydes
14 and 19, specific examples of retron 3.19
(7) Postema, M. H. D. Tetrahedron 1992, 48, 8545.
(8) (a) Haneda, T.; Goekjian, P.; Kim, S. H.; Kishi, Y. J. Org. Chem.
1992, 57, 490-498. (b) Wei, A.; Haudrechy, A.; Audin, C.; Jun, H.-S.;
Haudrechy-Bretel, N.; Kishi, Y. J. Org. Chem. 1995, 60, 2160. (c) Wei,
A.; Boy, K. M.; Kishi, Y. J. Am. Chem. Soc. 1995, 117, 9432-9436.
(9) Armstrong, R. W.; Sutherlin, D. P. Tetrahedron Lett. 1994, 35, 7743.
(10) Sutherlin, D. P.; Hughes R.; Stark, T. M.; Armstrong, R. W.
Manuscript in review.
(13) Hosomi, A.; Sakata, Y.; Sakurai, H. Tetrahedron Lett. 1984, 25,
2383.
(14) Derived in four steps from N-acetylglucosamine and described fully
in the supporting information.
(11) Armstrong, R. W.; Sutherlin, D. P.; Wolinski, L. Presented at the
31st Annual ACS Western Regional Meeting, San Diego, CA, October 18-
21, 1995.
(12) This process is parallel to Janda’s recursive deconvolution of
combinatorial libraries. Erb, E.; Janda, K. D.; Brenner, S. Proc. Natl. Acad.
Sci. U.S.A. 1994, 91, 11422.
(15) (a) Dyer, U. C.; Kishi, Y. J. Org. Chem. 1988, 53, 3383-3384. (b)
Kishi Y. Pure Appl. Chem. 1992, 64, 343-350.
(16) The stereochemistry of the protected allylic alcohol 13 was
elucidated by X-ray crystallography.
(17) Evans, D. A.; Ratz, A. M.; Huff, B. E.; Sheppard, G. S. J. Am.
Chem. Soc. 1995, 117, 3448-3467.
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