Thioglycuronides: Synthesis and application in the assembly of acidic oligosaccharides

Article abstract of DOI:10.1021/ol049380+

Partially protected thioglycuronic acids are prepared efficiently by chemo- and regioselective oxidation of the corresponding thioglycosides using the TEMPO/BAIB reagent combination. After esterification, the thioglycuronic acids proved to be useful as both donor and acceptor in sulfonium-mediated condensations toward acidic di- and trisaccharides.

Full text of DOI:10.1021/ol049380+

ORGANIC
LETTERS
2004
Vol. 6, No. 13
2165-2168
Thioglycuronides: Synthesis and
Application in the Assembly of Acidic
Oligosaccharides
Leendert J. van den Bos, Jeroen D. C. Code´e, John C. van der Toorn,
Thomas J. Boltje, Jacques H. van Boom, Herman S. Overkleeft, and
Gijsbert A. van der Marel*
Leiden Institute of Chemistry, Leiden UniVersity, P.O. Box 9502,
2300 RA Leiden, The Netherlands
g.marel@chem.leidenuniV.nl
Received April 6, 2004
ABSTRACT
Partially protected thioglycuronic acids are prepared efficiently by chemo- and regioselective oxidation of the corresponding thioglycosides
using the TEMPO/BAIB reagent combination. After esterification, the thioglycuronic acids proved to be useful as both donor and acceptor in
sulfonium-mediated condensations toward acidic di- and trisaccharides.
Uronic acids are present in a wide array of biologically
relevant oligosaccharides, polysaccharides, and glycoconju-
gates.1 Hence, flexible and straightforward synthesis routes
toward these important molecules should have a major impact
on research in glycobiology. Although it is well established
that thioglycosides are versatile synthons en route toward
such carbohydrate targets,2 approaches in which thio-
glycuronic acids are employed are scarce. This can be
explained by the lack of efficient synthetic protocols for the
preparation of suitably protected thioglycuronides.3 In ad-
dition, thioglycuronic acids have been shown to be rather
poor glycosyl donors, generally requiring the presence of
activating protecting groups.3d In our program directed
toward the development of efficient methodologies for the
preparation of biologically relevant oligosaccharides,4 we
recently reported a novel sequential glycosylation strategy
(Figure 1, route A).5 Our method is based on Ph2SO/Tf2O-
mediated condensation6 (I) of 1-hydroxyl donor 1 and
(3) The few methods known in the literature are mainly based on the
use of chromium-based oxidants: (a) Nakano, T.; Ito, Y.; Ogawa, T.
Tetrahedron Lett. 1990, 31, 1597-1600. (b) Nilsson, M.; Svahn, C.-M.;
Westman, J. Carbohydr. Res. 1993, 246, 161-172. (c) Goto, F.; Ogawa,
T. Tetrahedron Lett. 1993, 33, 5099-5102. (d) Garegg, P. J., Olsson, L.;
Oscarson, S. J. Org. Chem. 1995, 60, 2200-2204. (e) Magaud, D.;
Grandjean, C.; Doutheau, A.; Anker, D.; Shevchik, V.; Cotte-Pattat, N.;
Robert-Baudouy, J. Tetrahedron Lett. 1997, 38, 241-244. (f) Allanson, N.
M.; Liu, D.; Chi, F.; Jain, R. K.; Chen, A.; Ghosh, M.; Hong, L.; Sofia, M.
J. Tetrahedron Lett. 1998, 39, 1889-1892.
(4) Code´e, J. D. C.; Van der Marel, G. A.; Van Boeckel, C. A. A.; Van
Boom, J. H. Eur. J. Org. Chem. 2002, 23, 3954-3965.
(5) (a) Code´e, J. D. C.; Van den Bos, L. J.; Litjens, R. E. J. N.; Overkleeft,
H. S.; Van Boom, J. H.; Van der Marel, G. A. Org. Lett. 2003, 5, 1947-
1950. (b) Code´e, J. D. C.; Van den Bos, L. J.; Litjens, R. E. J. N.; Overkleeft,
H. S.; Van Boeckel, C. A. A.; Van Boom, J. H.; Van der Marel, G. A.
Tetrahedron 2003, 60, 1057-1064.
(1) (a) Glycochemistry: Principles, Synthesis, and Applications; Wang,
P. G., Bertozzi, C. P., Eds.; Marcel Dekker: New York, 2001; pp 425-
492. (b) For a recent review on the synthesis of glycosaminoglycans, see:
Yeung, B. K. S.; Chong, P. Y. C.; Petillo, P. A. J. Carbohydr. Chem. 2002,
21, 799-865.
(2) (a) For a review on the use of thioglycosides as glycosyl donors,
see: Garegg, P. J. AdV. Carbohydr. Chem. Biochem. 1997, 52, 179-205.
(b) Davis, B. G. J. Chem. Soc., Perkin Trans. 1 2000, 14, 2137-2160.
10.1021/ol049380+ CCC: $27.50 © 2004 American Chemical Society
Published on Web 05/22/2004

using TEMPO and an equimolar amount of BAIB as a co-
oxidant. Interestingly, this oxidation protocol could also be
applied to alcohols containing sulfo- and selenoethers. We
set out to establish whether this reagent combination could
be employed for the selective oxidation of suitably protected
thioglycosides to provide the corresponding thioglycuronic
acids. As the initial research objective, we evaluated the
compatibility of the TEMPO/BAIB system with thiogluco-
pyranosides 8 and 9 (Scheme 1). Treatment of ethyl 2,3,4-
Scheme 1
Figure 1. Glycosylation strategy toward acidic trisaccharides.
partially protected thioglycoside 2 to afford the corresponding
thiodisaccharide. In the next glycosylation event (II), suc-
cessive treatment of the intermediate thio function with
sulfonium triflate species 7a or 7b, generated in situ from
BSP/Tf2O7 or Ph2SO/Tf2O,8 respectively (see Figure 2), and
tri-O-benzyl-1-thio-â-D-glucopyranoside 8 with a catalytic
amount of TEMPO and excess BAIB in a mixture of
dichloromethane and water (2:1), followed by methylation
of the thus-formed carboxylate 10 with freshly prepared
diazomethane afforded thioglucuronide 12 in a rewarding
88% yield over the two steps. It should be noted that careful
monitoring of the reaction mixture by TLC and timely
quenching, with an aqueous thiosulfate solution, could
adequately prevent unwanted sulfoxide and/or sulfone forma-
tion. Following the same sequence of reactions, ethyl 2,3-
di-O-benzyl-1-thio-â-D-glucopyranoside 9 was converted into
methyl ester 13 in 85% (based on 9), demonstrating the
excellent chemo- and regioselective nature of this method.
The results of the TEMPO/BAIB oxidation of a variety
of thio- and selenoglycosides are summarized in Table 1.
Phenyl 2,3,4-tri-O-benzoyl-1-seleno-R-D-galactopyranoside
14 was also readily transformed, via acid 15, into
galacturonic ester 16 (entry 1). In the same way, subjection
of phenyl 2,3-O-isopropylidene-4-O-benzyl-1-thio-R-D-
mannopyranoside 17 to the two-step procedure produced
ester 19 (entry 2). The selectivity of our strategy in the
oxidation of a primary alcohol in the presence of both a
thioglycosidic linkage and a secondary alcohol is revealed
in entries 3-8. Both S-phenyl- and S-ethylthioglycosides can
be employed in our strategy, as is illustrated by the equally
efficient transformation of 20 and 21 into 24 and 25,
respectively. Furthermore, both the starting glycoside (glu-
cose, glucosamine, galactose, and idose) and the nature of
the protective groups (benzyl, benzoyl, isopropylidene, tert-
butyldimethylsilyl, azide, and phthalimide) can be readily
varied without having major implications on the outcome
of the oxidation step (all yields are within the range of 70-
90%).
Figure 2. Recently developed sulfonium triflate activator systems.
subsequent addition of a suitably protected nucleophile 3
afforded the desired trisaccharide. The potency of the novel
activator systems 7a and 7b in these syntheses encouraged
us to evaluate the highly unreactive thioglycuronides in the
aforementioned glycosylation sequence. This evidently called
for an efficient mode of synthesis to access a wide variety
of thioglycuronic acid synthons. We here disclose the 2,2,6,6-
tetramethyl-1-piperidinyloxyl, free radical (TEMPO)/[bis-
(acetoxy)-iodo]benzene (BAIB)-mediated chemo- and regio-
selective oxidation of readily available partially protected
thioglycosides as a powerful means to obtain the correspond-
ing thioglycuronic acids (Figure 1, route B).9 After esteri-
fication of the carboxylate functions, these partially protected
thioglycuronides 5 can, in the same way as key building
block 2, be incorporated in our strategy to furnish acidic
oligosaccharides.
Piancatelli and co-workers9 recently reported the oxidation
of primary alcohols into their corresponding aldehydes10
(6) (a) Garcia, B. A.; Poole, J. L.; Gin, D. Y. J. Am. Chem. Soc. 1997,
119, 7597-7598. (b) Garcia, B. A.; Gin, D. Y. J. Am. Chem. Soc. 2000,
122, 4269-4279.
(7) Crich, D.; Smith, M. J. Am. Chem. Soc. 2001, 123, 9015-9020.
(8) Code´e, J. D. C.; Litjens, R. E. J. N.; Den Heeten, R.; Overkleeft, H.
S.; Van Boom, J. H.; Van der Marel, G. A. Org. Lett. 2003, 5, 1519-
1522.
(9) De Mico, A.; Margarita, R.; Parlanti, L.; Vescovi, A.; Piancatelli, G.
J. Org. Chem. 1997, 62, 6974-6977.
(10) Use of high concentrations of water and 2 equiv of BAIB facilitates
the conversion of the aldehyde into the respective carboxylic acid: Epp, J.
B.; Widlanski, T. S. J. Org. Chem. 1999, 64, 293-295. See also ref 9.
As the next research objective, we set out to establish the
reactivity of the obtained thioglycuronates in sulfonium
triflate-mediated glycosylation reactions. The reactivity of
these thioglycuronic acids toward various activating systems
is considerably reduced compared to the corresponding
thioglycosides due to the electron-withdrawing effect of the
carboxyl function. Illustrative examples of this phenomenon
2166
Org. Lett., Vol. 6, No. 13, 2004

Scheme 2
Table 1. Regio- and Chemoselective Oxidation of
Thioglycosides
conditions prescribed by the Crich laboratory, higher activa-
tion temperatures and longer activation times were needed.12
Analogous results were obtained in the glycosylation of the
more reactive thiogalactoside donor 44 with acceptor 45
delivering diuronate 46.
Having established that thioglycuronates could be readily
applied as donors in the sulfonium activator-mediated
disaccharide synthesis, we turned our attention to their
implementation in the sequential chemoselective synthesis
of trisaccharide 50. This protected carbohydrate motive
corresponds to the (GlcpNAcR(1f4)-GlcpAR(1f2)Galf)
trisaccharide present in the capsular polysaccharide of the
Fungus Fusarium sp. M7-1.13 Activation of hemiacetal donor
47 with diphenylsulfonium bistriflate 7b in the presence of
tri-tert-butylpyrimidine (TTBP)14 (Scheme 3) as a base and
Scheme 3
a Conditions: 0.2 equiv TEMPO, 2.5 equiv BAIB, DCM/H2O (2:1), rt.
b Conditions: CH2N2, DMF, rt. c Isolated yields.
subsequent treatment with uronic acid acceptor 13 gave the
R-linked thiodisaccharide 48 as the sole product in a
gratifying 67% yield. In the second glycosylation event, 48
was smoothly activated under the agency of BSP/Tf2O and
were published by the groups of Garegg and Oscarson who
had to install at least two activating benzyl functions or a
3,4-tetraisopropyldisiloxyl group in the thioglucuronate
donors to obtain sufficient activation with dimethyl(methyl-
thio)sulfonium triflate (DMTST).3d,11 We reasoned that the
reactive benzenesulfinylpiperidino bistriflate 7a7 would be
sufficiently electrophilic for reaction with the highly “dis-
armed”, acylated donor 41 and the benzylated donor 44.
Indeed, preactivation of 41 occurred smoothly and subse-
quent addition of acceptor 42 afforded the corresponding
disaccharide 43 in good yield. Compared to the standard
(11) Krog-Jensen, C.; Oscarson, S. Carbohydr. Res. 1998, 308, 287-
296.
(12) Activation of the donor for 5 min at -60 °C revealed incomplete
activation of the donor glycoside. We therefore started the activation at
-60 °C and gradually warmed the reaction mixture to -40 °C within 15
min (see also ref 7).
(13) (a) Iwahara, S.; Suemori, N.; Ramli, N.; Takegawa, K. Biosci.
Biotech. Biochem. 1995, 59, 1082-1085. (b) Jikibara, T.; Takegawa, K.;
Iwahara, S. J. Biochem. 1992, 111, 225-229.
(14) Crich, D.; Smith, M.; Yao, Q.; Picione, J. Synthesis 2001, 323-
326.
Org. Lett., Vol. 6, No. 13, 2004
2167

condensed with partially protected galactono-1,4-lactone 4915
to give the desired trisaccharide 50 as an anomeric mixture
(R/â ) 4:1) in 35% yield.
of the anomeric center compared to the parent thioglycosides.
The yields observed in the presented examples are in the
range of 35-68%. However, we feel that the partial loss in
glycosylation efficiency is more than compensated by the
reduced number of protecting group manipulations required.
Current research efforts are aimed at the optimization of our
glycosylation procedure and its application in the synthesis
of more complex uronic acid-containing oligosaccharides.
In conclusion, we have presented a novel and efficient
strategy for the regio- and chemoselective oxidation of
thioglycosides to give the corresponding thioglycuronides.
In turn, these thioglycuronides proved to be useful as both
acceptors and donors in the synthesis of acidic oligosaccha-
rides as exemplified by the assembly of trisaccharide 50.
Further, the efficient BSP/Tf2O activator system proved to
be capable of activating even the highly deactivated donor
41. Our strategy nicely complements contemporary synthetic
efforts toward uronic acid-containing oligosaccharides, which
are often based on the introduction of the carboxylate
functions after oligosaccharide assembly. The efficiency of
oligosaccharide synthesis using these thioglycuronic acid
donors is somewhat compromised by the reduced reactivity
Acknowledgment. The authors thank Kees Erkelens en
Fons Lefeber for recording NMR spectra and Bertil Hofte
for measuring accurate mass spectra. This work was sup-
ported by The Netherlands Technology Foundation (STW)
and the Council for Chemical Sciences of The Netherlands
Organization for Scientific Research (CW-NWO).
Supporting Information Available: General procedures
and characterizations of all new compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
(15) For preparation of compound 49, galactono-1,4-lactone was sub-
sequently treated with (1) Me2C(OMe)2, p-TsOH, acetone; (2) TBDMSCl,
imidazole, DCM, 0°C; (3) BzCl, pyridine, 0 °C; and (4) TBAF, AcOH in
THF (62% over four steps).
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