group does not depart on its own, we have developed three
major activation pathways for their use in glycosylation
reactions (Scheme 1).7 In the first pathway, thiophilic
activating or deactivating the anomeric moiety through
changing the electronic environment around the anomeric
center. This would also provide an alternative to the
previously explored armed-disarmed6 and active-latent
glycosylation strategies.11,12
After glycosylation, a number of synthetic scenarios can
be envisaged. For example, the disaccharide could be cleaved
from the complex by ligand exchange and used in a
subsequent glycosylation as a glycosyl donor. Alternatively,
a temporary protecting group (P, Scheme 2) could be
removed and the resulting glycosyl acceptor unit used for
chain elongation.
Scheme 1. Activation Pathways for Thioimidate Glycosidation
To establish whether chemically stable transition metal
complexes could be formed from STaz glycosides, we chose
to examine the reaction of the per-benzoylated STaz glyco-
side 1a9 with PdBr2 (1-2 mol equiv) in the presence of 3 Å
molecular sieves in dry (CH2Cl)2. A very stable complex
1a2PdBr2, containing two sugar ligands, was formed quan-
titatively after 2 h at room temperature (Scheme 3). To
reagents (NIS/TMSOTf) serve to activate the anomeric
leaving group via complexation to the sulfur atom (pathway
A). In the second approach, electrophilic promoters such as
MeOTf target the thioimidoyl nitrogen (pathway B). Finally,
metal salt-based promoters (AgOTf or Cu(OTf)2) can
complex to both the sulfur and nitrogen atoms intra- or
intermolecularly (pathway C) and bring about anomeric
activation. Some of these promoters are already commonly
used for thioglycoside activation.10 However, it is the
possibility of using metal-salt-based activation that distin-
guishes the thioimidates from their S-alkyl/aryl counterparts.
In an effort to expand the scope of the oligosaccharide
synthesis in general and the STaz method in particular, we
wondered whether it would be possible to temporarily nullify
the reactivity of the thioimidoyl derivatives toward glyco-
sylation by reversible blocking of one or both of the
activation centers. For example, if the lone pair on the
nitrogen were temporarily deactivated (capped), this would
make promoter-assisted thioimidate activation via any of the
pathways shown in Scheme 1 a very unlikely process. One
possible way in which this could be achieved is if we were
to engage the STaz moiety in a stable, nonionizing metal
complex. Overall, this should allow chemoselective activation
of a “free” STaz leaving group (glycosyl donor) over a
deactivated (complexed, capped) STaz moiety (glycosyl
acceptor); the concepts are illustrated in Scheme 2. If such
an approach were successful, it might prove possible to
chemoselectively glycosylate without the necessity for
Scheme 3. Synthesis and X-ray Crystal Structure of a
Representative Palladium(II) Complex 1a2PdBr2
elucidate how the metal was attached to the sugar units, the
structure of 1a2PdBr2 was determined by X-ray crystal-
lography. It was found that attachment occurs via the nitrogen
atoms of the thiazoline rings (Pd-N (av) )2.009 (8) Å).13
In like fashion, the partially protected STaz glycosides 1c-g
Scheme 2. Outline of the Temporary Deactivation Concept
(10) Garegg, P. J. AdV. Carbohydr. Chem. Biochem. 1997, 52, 179-
205.
(11) Roy, R.; Andersson, F. O.; Letellier, M. Tetrahedron Lett. 1992,
33, 6053-6056.
(12) Kim, K. S.; Kim, J. H.; Lee, Y. J.; Lee, Y. J.; Park, J. J. Am. Chem.
Soc. 2001, 123, 8477-8481.
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Org. Lett., Vol. 6, No. 24, 2004