ORGANIC
LETTERS
2003
Vol. 5, No. 23
4365-4368
Synthesis of Lactose-Based S-Linked
Sialylmimetics of r(2,3)-Sialosides
Angela Liakatos, Milton J. Kiefel, and Mark von Itzstein*
Institute for Glycomics, Griffith UniVersity, Gold Coast Campus,
PMB 50 Gold Coast Mail Centre, Queensland 9726, Australia
Received September 10, 2003
ABSTRACT
A new approach toward the synthesis of lactose-based S-linked sialylmimetics of r(2,3)-linked sialosides is described. These compounds,
represented by the general structure 3, were prepared from methyl â-D-lactoside in 11 steps. It was found that the choice of protecting group
was crucial to allow the efficient introduction of sulfur at the 3-position of the galactose ring.
Sialic acids are a family of carbohydrates that, as R-keto-
sidically linked components of cell surface glycoconjugates,
play significant roles in a number of important biological
processes.1-4 Typically found at the terminus of these
glycoconjugates, sialic acids are ideally located to participate
in carbohydrate-protein interactions that mediate a range
of biological processes. These processes include cell-cell
adhesion and communication, microbial pathogenesis, and
cellular response to changes in environment.1-4 Specific
examples of these interactions include the binding of
influenza virus haemagglutinin to cell-surface sialic acids5
and the interaction of selectins with sialyl Lewis x during
the recruitment of leukocytes in the inflammation process.6,7
The growing realization of the importance of R-ketosid-
ically linked sialic acids in biological processes has generated
intensive research into sialic acid chemistry and biochem-
istry.8-11 The complexity associated with the synthesis of
structurally modified sialosides as potential inhibitors or
probes of sialic acid-recognizing proteins8,9,12 has led to great
interest in the development of compounds that mimic the
key components of sialosides involved in important interac-
tions with biomolecules. These sialylmimetics are structurally
simpler than the sialoside upon which they are based, making
them more amenable to synthesis as well as having poten-
tially improved pharmacological profiles.6,8,13
N-Acetylneuraminic acid R-(2,3)-linked to galactose (1)
is a commonly found epitope in a number of important cell-
surface glycoconjugates. This epitope is believed to be the
minimum sequence required for the binding of rotavirus to
host cells14 and is overexpressed on the cell surface of some
metastatic cancers as a result of the upregulation of R(2,3)-si-
alyltransferases.15 N-Acetylneuraminic acid R(2,3)-linked to
galactose (1) is also identified as a key recognition sequence
of the trypanosomal R(2,3)-trans-sialidase.16 This same se-
(9) Zbiral, E. In Carbohydrates: Synthetic Methods and Applications
in Medicinal Chemistry; Ogura, H., Hasegawa, A., Suami, T., Eds.; VCH:
New York, 1992; pp 304-339.
(1) Schauer, R.; Kamerling, J. P. In Glycoproteins II; Montreuil, J.,
Vliegenthart, J. F. G., Schachter, H., Eds.; Elsevier: Amsterdam, 1997; pp
243-402.
(10) Boons, G.-J.; Demchenko, A. V. Chem. ReV. 2000, 100, 4539-4565.
(11) Danishefsky, S. J.; Allen, J. R. Angew. Chem., Int. Ed. 2000, 39,
836-863.
(2) Biology of the Sialic Acids; Rosenberg, A., Ed.; Plenum Press: New
York, 1995.
(3) Bertozzi, C. R.; Kiessling, L. L. Science 2001, 291, 2357-2364.
(4) Angata, T.; Varki, A. Chem. ReV. 2002, 102, 439-469.
(5) Skehel, J. J.; Wiley: D. C. Annu. ReV. Biochem. 2000, 69, 531-
569.
(12) von Itzstein, M.; Kiefel, M. J. In Carbohydrates in Drug Design;
Witczak, Z. J., Nieforth, K. A., Eds.; Marcel Dekker: New York, 1997; pp
39-82.
(13) Barchi, J. J., Jr. Curr. Pharm. Des. 2000, 6, 485-501.
(14) Delorme, C.; Bru¨ssow, H.; Sidoti, J.; Roche, N.; Karlsson, K.-A.;
Neeser, J.-R.; Teneberg, S. J. Virol. 2001, 75, 2276-2287.
(15) See for example: Zhou, Q.; Hakomori, S.-i.; Kitamura, K.; Igarashi,
Y. J. Biol. Chem. 1994, 269, 1959-1965.
(6) Sears, P.; Wong, C.-H. Angew. Chem., Int. Ed. 1999, 38, 2300-2324.
(7) Simanek, E. E.; McGarvey, G. J.; Jablonowski, J. A.; Wong, C.-H.
Chem. ReV. 1998, 98, 833-862.
(8) Kiefel, M. J.; von Itzstein, M. Chem. ReV. 2002, 102, 471-490.
10.1021/ol035733d CCC: $25.00 © 2003 American Chemical Society
Published on Web 10/21/2003