efficacy ligand analogues, for example, with enhanced
affinity for bacterial toxins3b or cancer-associated cell-surface
receptors.5 In only a few cases is a structural knowledge of
the basis for multivalent interaction available, and thus most
effective synthetic ligands have been identified through
screening numbers of ligand types or serendipity.
It is also evident from several studies that the mode of
multivalent binding can vary between ligands/ligand types
and that higher-order organization can play a role in the
aggregation of ligands at surfaces. Advances in surface
immobilization of synthetic multivalent carbohydrates have
allowed the cluster glycoside effect to be further investi-
gated.6 This has recently begun to be exploited in the
connection of multivalent ligands to nanoparticles and
quantum dots.7 It is thus important to have syntheses of
multivalent architectures amenable to practicable diversity
but which also, ideally, are designed to enable surface
immobilization and other conjugation.
separately, and employing conserved attachment chemistry
for any saccharides also circumvents any significant differ-
ences in reactivity or selectivity between different saccharides
(in contrast to O-glycosylation attachments).
This letter reports the synthesis of the scaffold/core units,
C-glycosidic components, and the combination of units to
provide variable multivalent systems.
The core scaffolds for this study were prepared from
tris(hydroxymethyl)aminomethane 1. To illustrate modular-
ity, we demonstrate the synthesis of a minimal core type
derived from 1 and of an ethylene diamine extended core
and their respective coupling to different C-glycoside
modules with varying length spacers preattached. The first
truncated core target was trisamine 5, prepared through
N-protection of 1 and allylation of the hydroxyl units8
(Scheme 1). Subsequent hydroboration/oxidation of the
We report here a synthetic approach to C-glycosidic
multisugar-bearing ligands designed to enable diversification
by variation of several modular components to deliver a
virtual matrix of diverse carbohydrate ligand arrays. Figure
1 shows a generic model structure. The A and B modules
Scheme 1. Synthesis of the Tris(aminopropyl) Core
Figure 1. Generic multivalent C-glycosidic ligand representation.
terminal alkenes (with in situ acetylation-deacetylation)
provided triol 3.
Triol 3 was then converted to phthalimide derivative 4
with subsequent hydrazinolysis of this material furnishing
target 5.9 Unfortunately, purification of this material was
problematic (due to a hydrazinolysis by-product), and thus
an alternative approach was sought. This objective was
achieved by proceeding via trisnitrile intermediate 610
obtained from triol 1 in high yield, through O-selective
Michael addition to acrylonitrile.
Since the amino group needed protection and would need
further elaboration with linker units for diversification (i.e.,
linking to terminus D, Figure 1), the amine was protected
using a motif that addressed both requirements simulta-
neously. Thus, reaction with succinic anhydride followed by
esterification afforded amide 7. The strategy envisaged amide
coupling of the core to C-glycosides bearing extended
carboxylates, thus the nitriles were converted to amines.
Direct conversion to the parent, shorter trisamine 9 was
are independently variable to enable changes in spatial array
and/or changes in ligand rigidity (and thus an A × B matrix).
The C unit is a common trisalkyl core, and an alkyl/polyether/
amido “tail” unit is linked from the core nitrogen via a
succinimidyl coupling to introduce terminus D to allow direct
surface attachment or attachment of other motifs for im-
mobilization studies or conjugations. This end linker module
also has highly variable structural options.
C-Glycosidic attachment provides anomerically stable
ligands but also provides saccharide-type independent chem-
istry for attachment to the core, obviating any anomeric
stereochemical variability from the multivalent coupling step.
Different anomerically pure C-glycosides can be prepared
(5) Sliedregt, L. A. J. M.; van Rossenberg, S. M. W.; Autar, R.;
Valentijn, A. R. P. M.; van der Marel, G. A.; van Boom, J. H.; Piperi, C.;
van der Merwe, P. A.; Kuiper, J.; van Berkel, T. J. C.; Biessen, E. A. L.
Bioorg. Med. Chem. 2001, 9, 85–97.
(6) Suda, Y.; Arano, A.; Fukui, Y.; Koshida, S.; Wakao, M.; Nishimura,
T.; Kusomoto, S.; Sobel, M. Bioconjugate Chem. 2006, 17, 1125–1135.
(7) (a) Mukhopadhyay, B.; Martins, M. B.; Karamnska, R.; Russell,
D. A.; Field, R. A. Tetrahedron Lett. 2009, 50, 886–889. (b) Chien, Y.-Y.;
Jan, M.-D.; Adak, A. K.; Tseng, H.-C.; Lin, Y.-P.; Chen, Y.-J.; Wang, K.-
T.; Chen, C.-T.; Chen, C.-C.; Lin, C.-C. ChemBioChem 2008, 9, 1100–
1109.
(8) Seto, C. T.; Mathias, J. P.; Whitesides, G. M. J. Am. Chem. Soc.
1993, 115, 1321–1329.
(9) Ternon, M.; Dy´`ıaz-Mocho´n, J. J.; Belsom, A.; Bradley, M. Tetra-
hedron 2004, 60, 8721–8728.
(10) Cheedarala, R. K.; Sunkara, V.; Park, J. W. Synth. Commun. 2009,
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Org. Lett., Vol. 12, No. 22, 2010
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Miller, Gavin J.
