4-(Pyridin-2-yl)thiazol-2-yl thioglycosides as bidentate ligands for oligosaccharide synthesis via temporary deactivation

Article abstract of DOI:10.1039/b810569c

This study focusses on a new concept for oligosaccharide synthesis based on 4-(pyridin-2-yl)thiazol-2-yl thioglycosides that can either act as effective glycosyl donors or can be deactivated by stable bidentate complexation with palladium(ii) bromide. The Royal Society of Chemistry.

Full text of DOI:10.1039/b810569c

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4-(Pyridin-2-yl)thiazol-2-yl thioglycosides as bidentate ligands for
oligosaccharide synthesis via temporary deactivationw
Papapida Pornsuriyasak, Nigam P. Rath and Alexei V. Demchenko*
Received (in College Park, MD, USA) 23rd June 2008, Accepted 28th August 2008
First published as an Advance Article on the web 1st October 2008
DOI: 10.1039/b810569c
This study focusses on a new concept for oligosaccharide syn-
thesis based on 4-(pyridin-2-yl)thiazol-2-yl thioglycosides that
can either act as effective glycosyl donors or can be deactivated
by stable bidentate complexation with palladium(II) bromide.
Traditional linear approaches for oligosaccharide assembly are
cumbersome, and consequently the availability of complex
glycostructures remains insufficient to address the challenges
of modern glycosciences.1–4 Recent improvements for oligo-
saccharide synthesis, i.e. selective activation of one leaving group
over another5–9 or chemoselective activation of building blocks
Scheme 1 Temporary deactivation concept.
wherein reactivity is dictated by the nature of protecting
groups,10–13 significantly shorten oligosaccharide assembly.
to the marginal stability of the monodentate Pd(II)STaz
Nevertheless, these expeditious approaches14 and even
complex and its propensity to decomplex.
high-throughput automated15,16 or one-pot technologies17,18
To address this challenge, we investigated a series of novel
are still far from being comprehensively applicable.
anomeric moieties that would be capable of forming more
We have already reported a temporary deactivation concept
stable bidentate complexes, as depicted in Fig. 1. Herein we
for oligosaccharide synthesis based on the ability of S-thiazolinyl
report our preliminary investigation of this concept, focusing
(STaz) glycosides to be engaged in stable non-ionizing transition
primarily on 4-(pyridin-2-yl)thiazol-2-yl (PT) thioglycosides as
metal complexes.19 As depicted in Scheme 1, this strategy allows
glycosyl donors and as complexed glycosyl acceptors.
chemoselective activation of the ‘‘free’’ STaz (or other) moiety on
We found that bromide 1 serves as a suitable precursor for
the glycosyl donor B over the deactivated (capped) STaz moiety
the synthesis of SPT glycosides upon reaction with readily
on the glycosyl acceptor A. Upon glycosylation, the disaccharide
accessible thiolate 2 (Scheme 2). The requisite SPT glycoside 3,
C is released from the complex to provide ‘‘free’’ disaccharide D,
obtained in 99% yield, was then converted into benzylated
which can be directly used as a glycosyl donor for subsequent
glycosyl donor 4. This transformation clearly demonstrated
transformations.
the compatibility of the SPT moiety with strongly basic
What remained unexplored is the ability to carry out the
reaction conditions (MeONa or NaH). The peracetate 3 was
multistep synthesis—it would be advantageous if upon
also converted into a glycosyl acceptor via intermediate 5, as
glycosidation, C could be converted into an acceptor E by
shown in Scheme 2.
removing a strategically placed substituent (P). The latter
The complexation of 5 with PdBr2 took place quantitatively
could then couple with the donor B to form the trisaccharide
and the resulting complex was sufficiently stable to detrityla-
and consequently higher oligosaccharides upon reiteration of
tion conditions to afford acceptor 6 (see Fig. 2 for crystal
the deprotection–glycosylation sequence. Indeed, the possibi-
structure). We believe that this observation alone may serve as
lity of achieving a desired oligosaccharide employing only one
a viable proof of the bidentate concept, since the first genera-
class of a leaving group, irrespective of the nature of the
tion monodentate STaz ligands were found to be unstable to
protective groups, would be very attractive. This approach
detritylation. The glycosyl acceptor 6 was then glycosylated
should also allow for bidirectional20,21 (e.g. D + A) and
with glycosyl donor 4 in the presence of silver triflate. Upon
convergent22,23 (e.g. D + E) couplings. Unfortunately, our
subsequent decomplexation with NaCN, the requisite di-
attempts to apply this idea to STaz glycosides have failed due
saccharide 7 was obtained in 90% yield. It should be noted that
Department of Chemistry and Biochemistry, University of
Missouri—St. Louis, One University Boulevard, St. Louis, Missouri
63121, USA. E-mail: demchenkoa@umsl.edu
w Electronic supplementary information (ESI) available: Experimental
procedures for the synthesis of all new compounds and their 1H and
13C NMR spectra, as well as the structure and geometrical parameters
for 6. CCDC reference number 693543. For ESI and crystallographic
data in CIF or other electronic format see DOI: 10.1039/b810569c
Fig. 1 Anomeric thiomoieties for bidentate ligation.
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Scheme 2 Synthesis/evaluation of SPT donor 4 and acceptor 6.
Reagents and conditions: (i) Na/MeOH; (ii) MeCN; (iii) 1. MeONa/
MeOH, 2. BnBr/NaH, DMF; (iv) 1. NaOMe/MeOH, 2. TrCl, C5H5N,
3. BzCl; (v) 1. PdBr2, 3 A MS, 1,2-DCE, 2. 10% TFA/wet DCM, 0 1C;
(vi) 1. AgOTf, 3 A MS, DCM, 2. NaCN, acetone.
Scheme 3 Synthesis of pneumococcal oligosaccharides.
immunogenic due to the abundance of similar sequences in
mammalian tissues.27 This complicates its use as vaccine, and
as a result, scientists throughout the world have already turned
their attention to the chemical synthesis of SPn14 oligo-
saccharides and derivatives thereof.28–31 The branched tetra-
saccharide repeating unit of SPn14 consists of lactose linked to
the C-6 of lactosamine.
To perform this synthesis, we obtained the key building
blocks 8,32 9, and 11 (Scheme 3). The synthesis of 9 was
performed starting from known triacetyl-N-phthalimido
bromide,33 whereas lactose donor 11 was obtained from the
corresponding ethyl thioglycoside.31 The STaz donor 8 was
then coupled with the complexed acceptor 9 in the presence of
AgOTf followed by desilylation with TBAF to allow the
disaccharide acceptor 10. The latter was then coupled with
the lactose donor 11 to afford the SPn14 tetrasaccharide repeat
unit 12.
Fig. 2 X-Ray crystal structure of the acceptor complex 6. Projection
view of the molecule with 50% thermal ellipsoids—the disordered
component and solvent have been omitted for clarity. Selected crystallo-
graphic parameters for 6: Empirical formula C38H36Br2N2O10PdS2;
formula weight 1011.03; monoclinic; space group C2, Z = 4. Unit cell
dimensions: a = 26.134(2), b = 6.6651(5), c = 26.550(3) A, b =
118.580(4)1, volume 4061.1(7) A3; number of reflections collected
41 064; independent reflections 7012 [R(int) = 0.064]; final R indices:
R1 [I 4 2s(I)] = 0.0431, wR2 (all data) = 0.0951. CCDC # 693543.
For the subsequent convergent elongation, one portion of
tetrasaccharide 12 was treated with NaCN to afford glycosyl
donor 13, whereas another portion of 12 was treated with 10%
TFA to afford glycosyl acceptor 14. The coupling of 13 and 14
followed by decomplexation under the standard reaction
conditions afforded octasaccharide 15.
yields achieved with the STaz mediated temporary deactiva-
tion were significantly lower.19
To explore the scope of our concept, we investigated major
aspects of the SPT methodology. First, we determined that the
SPT–PdBr2 complex is also stable under standard conditions
for silyl group introduction/cleavage, tritylation, acylation/
deacylation, and acetal formation, reductive opening and
cleavage.24 Second, we determined the applicability of this
concept to other classes of glycosyl donors including trichloro-
acetimidates, thioimidates, and alkyl/aryl thioglycosides.25
Third, both primary and secondary glycosyl acceptors bearing
the complexed SPT moiety were obtained and tested accord-
ingly (see ESIw).
The versatility of the approach developed was illustrated by
the synthesis of medicinally relevant oligosaccharides of
Streptococcus pneumoniae serotype 14 (SPn14), the most pre-
valent cause of invasive pneumococcal disease worldwide.26
The bacterial isolate of SPn14 polysaccharide is poorly
In conclusion, we have developed a new approach to
expeditious oligosaccharide assembly. This method comple-
ments the advantageous features that made effective strategies
such as orthogonal, armed–disarmed, bidirectional, and
convergent, very attractive. In addition, as illustrated by the
synthesis of oligosaccharide 15, the SPT-mediated approach
allows for the flexible operation (and the interchange) of the
different strategies upon demand. Thus, selective activation is
executed for the synthesis of 10 and 12, whereas fundamentals
of chemoselective, convergent, and bi-directional strategies are
executed during the transformation of 12 into 15. It is to be
expected that the efficient synthesis of pneumococcal oligo-
saccharide 15 reported herein will significantly contribute to
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the international scientific effort dealing with the synthesis of
fully synthetic vaccines.
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The authors thank NIGMS (GM077170) for financial
support of this work and NSF for grants to purchase
equipment (CHE-9974801, CHE-9708640, CHE-9309690,
CHE-0420497). Dr R. E. K. Winter and Mr J. Kramer
(UM—St. Louis) are thanked for HRMS determinations.
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