A novel strategy for oligosaccharide synthesis via temporarily deactivated s-thiazolyl glycosides as glycosyl acceptors

Article abstract of DOI:10.1021/ol048043y

(Chemical equation presented) A new glycosylation strategy that allows chemoselective activation of the S-thiazolyl (STaz) moiety of a glycosyl donor over the temporarily deactivated glycosyl acceptor, bearing the same anomeric group, has been developed.

Full text of DOI:10.1021/ol048043y

ORGANIC
LETTERS
2004
Vol. 6, No. 24
4515-4518
A Novel Strategy for Oligosaccharide
Synthesis via Temporarily Deactivated
S-Thiazolyl Glycosides as Glycosyl
Acceptors
Papapida Pornsuriyasak, Umesh B. Gangadharmath, Nigam P. Rath, and
Alexei V. Demchenko*
Department of Chemistry and Biochemistry, UniVersity of Missouri-St. Louis,
One UniVersity BouleVard, St. Louis, Missouri 63121
demchenkoa@umsl.edu
Received September 25, 2004
ABSTRACT
A new glycosylation strategy that allows chemoselective activation of the S-thiazolyl (STaz) moiety of a glycosyl donor over the temporarily
deactivated glycosyl acceptor, bearing the same anomeric group, has been developed. This deactivation is achieved by engaging of the STaz
moiety of the glycosyl acceptor into a stable palladium(II) complex. Therefore, obtained disaccharides are then released from the complex by
simple ligand exchange.
An explosive growth of the field of glycobiology has
stimulated interest in the synthesis of a large number of
biologically and therapeutically important glycoconjugates
and the improvement of glycosylation methods.1-4 In recent
years, convergent synthetic strategies where one type of
leaving group is selectively activated over another have come
to the fore.5 Slightly differently, the armed-disarmed ap-
proach allows chemoselective activation of the armed gly-
cosyl donor over the disarmed acceptor, both bearing the
same leaving group.6 The deactivating effect is achieved by
the use of appropriate protecting groups: acyl to disarm, and
benzyl to arm. Here we report a conceptually novel method
for oligosaccharide synthesis that involves temporary disarm-
ing of a leaving group in the glycosyl acceptor by its external
deactivation.
As a part of a program to develop new methods and
strategies for convergent oligosaccharide synthesis, we
became interested in glycosyl thioimidates, a class of
glycosyl donors with the generic leaving group SCR1dNR2.
We have already reported the synthesis of S-benzoxazolyl
(SBox)7,8 and S-thiazolyl (STaz)9 glycosides and evaluated
them in stereoselective glycosylations and convergent oligo-
saccharide synthesis. Considering the multifunctional char-
acter of the thioimidoyl moiety, and the fact that this leaving
(1) Toshima, K.; Tatsuta, K. Chem. ReV. 1993, 93, 1503-1531.
(2) Boons, G. J. Contemp. Org. Synth. 1996, 3, 173-200.
(3) Davis, B. G. J. Chem. Soc., Perkin Trans. 1 2000, 2137-2160.
(4) Nicolaou, K. C.; Mitchell, H. J. Angew. Chem., Int. Ed. 2001, 40,
1576-1624.
(5) Boons, G. J. Tetrahedron 1996, 52, 1095-1121.
(6) Mootoo, D. R.; Konradsson, P.; Udodong, U.; Fraser-Reid, B. J. Am.
Chem. Soc. 1988, 110, 5583-5584.
(7) Demchenko, A. V.; Malysheva, N. N.; De Meo, C. Org. Lett. 2003,
5, 455-458.
(8) Demchenko, A. V.; Kamat, M. N.; De Meo, C. Synlett 2003, 1287-
1290.
(9) Demchenko, A. V.; Pornsuriyasak, P.; De Meo, C.; Malysheva, N.
N. Angew. Chem., Int. Ed. 2004, 43, 3069-3072.
10.1021/ol048043y CCC: $27.50
© 2004 American Chemical Society
Published on Web 11/02/2004

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.
4516
Org. Lett., Vol. 6, No. 24, 2004

Table 1. Synthesis of the Disaccharide Derivatives 4-6 via a New Strategy Based on the Temporary Deactivation Concept
entry
donor
acceptor
promoter
solvent
temperature
time
16 h
20 h
19 h
16 h
6 h
20 h
2 h
5 min
5 min
20 min
40 min
30 min
product
yield, %
R/â ratio
1
2
3
4
5
6
7
8
9
1a
1a
1b
1b
1b
1b
2a
2b
2b
2b
3a
3b
1c2PdBr2
1d2PdBr2
1c2PdBr2
1d2PdBr2
1e2PdBr2
1f2PdBr2
1c2PdBr2
1c2PdBr2
1c2PdBr2
1g2PdBr2
1c2PdBr2
1c2PdBr2
MeOTf
MeOTf
Cu(OTf)2
NIS/TfOH
MeOTf
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
MeCN
DCE
DCE
DCE
-20 °C f rt
-40 °C f rt
-20 °C f rt
-40 °C f rt
-40 °C f rt
-40 °C f rt
-20 °C
-20 °C
-20 °C
rt
rt
4a
4b
4c
4d
5
6a
4a
4c
4c
6b
4a
4c
63
56
72
61
52
48
86
72
69
63
76
78
â only
â only
2.0/1
1.8/1
2.2/1
2.5/1
â only
1.3/1
â only
2.0/1
â only
1/3.6
MeOTf
NIS/TfOH
NIS/TfOH
NIS/TfOH
NIS/TfOH
Cu(OTf)2
Cu(OTf)2
10
11
12
rt
were employed for the synthesis of glycosyl acceptors
1c2PdBr2-1g2PdBr2. These were found to be of sufficient
purity to be used in subsequent glycosylation without any
adverse effects.14
Having synthesized these palladium(II) complexes, we
performed a number of coupling experiments (Table 1). First
of all, we demonstrated that either benzoylated (1a) or
benzylated STaz glycosyl donor (1b) could be activated over
temporarily deactivated benzoylated or benzylated 6-hy-
droxyl glycosyl acceptors (1c2PdBr2 and 1d2PdBr2, respec-
tively). Upon glycosylation, the obtained disaccharides were
released from the complex by treatment with NaCN in
acetone. As a result, a range of (1f6)-linked disaccharides
4a-d were isolated in moderate to good yield (entries 1-4,
(13) Single-crystal structure was solved and refined in monoclinic space
group C2. Cell parameters: a ) 43.8030(8) Å, b ) 14.8246(3) Å, c )
26.4865(5) Å, â ) 108.874(1)°, V ) 16274.6(5) Å3, z ) 8, R(F) ) 0.095,
wR(F2) ) 0.200 for 28628 independent reflections, 1687 parameters and
10 restraints. A Bruker SMART 1K CCD diffractometer with Mo KR
radiation (λ ) 0.71073 Å) was used for data collection at 160(2) K.
(14) Palladium(II) complexes have an extended shelf life and are of
sufficient stability to be purified by chromatography or crystallization.
Org. Lett., Vol. 6, No. 24, 2004
4517

Table 1). Our results provide encouraging support for the
temporary deactivation effect.
Clearly, our results provide solid evidence for the pref-
erential activation of one leaving group over another without
the requirement for altering the protecting group pattern. An
attractive feature of this strategy is that it does not rely on
protecting groups to control the leaving group ability and,
thus, glycosyl donor reactivity. Since protecting groups also
control the anomeric stereoselectivity of glycosylation, the
new approach offers more flexibility in this respect.
We next set about examining whether it would be possible
to activate an electronically “disarmed” (benzoylated) gly-
cosyl donor 1a over an otherwise “armed” (benzylated)
glycosyl acceptor 1d2PdBr2 (entry 2).15 In this case, the
complexed, Pd-deactivated S-thiazolyl leaving group was
found to be entirely inert. Each coupling experiment was
performed in the presence of different promoters, most
commonly AgOTf, MeOTf, Cu(OTf)2, or NIS/TfOH. How-
ever, only those resulting in better yields are listed. Similarly,
(1f4)- and (1f3)-linked disaccharides 5 and 6a were
obtained (entries 5 and 6).16
Acknowledgment. The authors thank the University of
Missouri-St. Louis for financial support and NSF for grants
to purchase the NMR spectrometer (CHE-9974801), the mass
spectrometer (CHE-9708640), and the X-ray diffractometer
(CHE-9309690) used in this work. We also thank Dr. J.
Wilking for assistance with 500 MHz NMR experiments,
and Dr. R. Winter and Mr. J. Kramer for HRMS determina-
tions.
(15) As anticipated, the attempted coupling of 1a with uncomplexed 1d
resulted in the formation of the 1,6-anhydro derivative, a product of the
intramolecular self-condensation of 1d. Similar precedents were previously
reported; for example, see: Klimov, E. M.; Malysheva, N. N.; Demchenko,
A. V.; Makarova, Z. G.; Zhulin, V. M.; Kochetkov, N. K. Dokl. Akad.
Nauk 1989, 309, 110-114.
(16) In some cases the yields were compromised due to the trans-ligation
(partial donor-acceptor exchange) that occurs prior to glycosylation. Most
typically, the highest ligand exchange rates were achieved with electronically
activated (benzylated) acceptors in the presence of AgOTf.
Supporting Information Available: Experimental pro-
cedures for the synthesis of 1c-f, 4a-d, 5, and 6a and their
1H and 13C NMR spectra. This material is available free of
charge via the Internet at http://pubs.acs.org.
(17) Dasgupta, F.; Garegg, P. J. Acta Chem. Scand. 1989, 43, 471-475.
(18) Steinborn, D.; Junicke, H. Chem. ReV. 2000, 100, 4283-4317.
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