Sequential one-pot glycosylations using 1-hydroxyl and 1-thiodonors

Article abstract of DOI:10.1021/ol034528v

(Matrix presented) A novel sequential glycosylation procedure is described that combines the use of 1-hydroxyl and thiodonors. The Ph₂SO/Tf ₂O-mediated dehydrative condensation of 1-hydroxyl donors with thioglycosides affords in good

Full text of DOI:10.1021/ol034528v

ORGANIC
LETTERS
2003
Vol. 5, No. 11
1947-1950
Sequential One-Pot Glycosylations
Using 1-Hydroxyl and 1-Thiodonors
Jeroen D. C. Code´e, Leendert J. van den Bos, Remy E. J. N. Litjens,
Herman S. Overkleeft, Jacques H. van Boom, and Gijs 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 March 26, 2003
ABSTRACT
A novel sequential glycosylation procedure is described that combines the use of 1-hydroxyl and thiodonors. The Ph2SO/Tf2O-mediated
dehydrative condensation of 1-hydroxyl donors with thioglycosides affords in good yield the thiodisaccharides, which in turn can be activated
by the same activator system to furnish trisaccharides. The r-Gal epitope and a hyaluronan trisaccharide were efficiently assembled in a
one-pot procedure.
The development of new and efficient strategies for the
assembly of oligosaccharides and glycoconjugates is an
intensive field of research.1 The synthesis of oligosaccharides
is traditionally a time-consuming process, mainly due to the
extensive need for protective group manipulations. The
majority of contemporary research in this field is therefore
focused on the development of glycosylation approaches in
which the number of synthetic and purification steps is
reduced. Recent solution-phase methodologies that omit the
need for the intermediate installation of a suitable anomeric
leaving group and/or protecting group manipulations include
chemoselective,2 orthogonal,3 iterative,4 and one-pot glyco-
sylations.5 The rate of success of these methodologies is
highly dependent on the selected glycosylation procedure.
In this framework, our attention was attracted by the work
of the groups of Gin and Crich, who developed two new
sulfonium activator systems (2a and 2b in Figure 1) for the
activation of 1-hydroxy6 and thiodonors,7 respectively.
We recently established8 that 2a and 2b can be imple-
mented in a sequential glycosylation procedure in which
Green, L. G.; Hahn, M. G.; Hinzen, B.; Ince, S. J.; Ley, S. V.
Tetrahedron: Asymmetry 2000, 11, 173-197. (g) Fridman, M.; Solomon,
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Takahashi, T. Org. Lett. 2002, 4, 4213-4216. (b) Demchenko, A. V.;
Malysheva, N. N.; De Meo, C. Org. Lett. 2003, 5, 455-458.
(4) (a) Friesen, R. W.; Danishefsky, S. J. J. Am. Chem. Soc. 1989, 111,
6656-6660. (b) Nguyen, H. M.; Poole, J. L.; Gin, D. Y. Angew. Chem.,
Int. Ed. 2001, 40, 414-417. (c) Yamago, S.; Yamada, T.; Hara, O.; Ito,
H.; Mino, Y.; Yoshida, J.-I. Org. Lett. 2001, 3, 3867-3870.
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C.-H. Angew. Chem., Int. Ed. 2002, 41, 4087-4090. (c) Mong, K.-K. T.;
Lee, H.-K.; Duro´n, S. G.; Wong, C.-H. Proc. Natl. Acad. Sci. U.S.A. 2003,
100, 797-802.
(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) (a) Crich, D.; Smith, M. J. Am. Chem. Soc. 2001, 123, 9015-9020.
(b) Crich, D.; Li, H. J. Org. Chem. 2001, 67, 4640-4646. For related studies,
see: (c) Crich, D.; Sun, S. Tetrahedron 1998, 54, 8321-8348. (d) Crich,
D.; Smith, M. Org. Lett. 2000, 2, 4067-4069. (e) Litjens, R. E. J. N.;
Leeuwenburgh, M. A.; van der Marel, G. A.; van Boom, J. H. Tetrahedron
Lett. 2001, 42, 8693-8696.
(1) (a) Carbohydrates in Chemistry and Biology; Ernst, B., Hart, G. W.,
Sinay¨, P., Eds.; Wiley-VCH: Weinheim, Germany, 2000; Vol. 1, Chapters
2-9. (b) Jung, K.-H.; Schmidt, R. R. Chem. ReV. 2000, 100, 4423-4442.
(c) Davis, B. G. J. Chem. Soc., Perkin Trans. 1 2000, 2137-2160. (d)
Garegg, P. J. AdV. Carbohydr. Chem. Biochem. 1997, 52, 179-205. (e)
Boons, G.-J. Tetrahedron 1996, 52, 1095-1121. (f) Schmidt, R. R.; Kinzy,
W. AdV. Carbohydr. Chem. Biochem. 1994, 50, 21-123. (g) Danishefsky,
S. J.; Bilodeau, M. T. Angew. Chem., Int. Ed. Engl. 1996, 35, 1380-1419.
(h) Toshima, K.; Tatsuta, K. Chem. ReV. 1993, 93, 1503-1531.
(2) (a) Douglas, N. L.; Ley, S. V.; Lu¨cking, U.; Warriner, S. L. J. Chem.
Soc., Perkin Trans. 1 1998, 51-65. (b) Zhang, Z.; Ollmann, I. R.; Ye,
X.-S; Wischnat, R.; Baasov, T.; Wong, C.-H. J. Am. Chem. Soc. 1999, 121,
734-753. (c) Zhu, T.; Boons, G.-J. Org. Lett. 2001, 3, 4201-4203. (d)
Mootoo, D. R.; Konradsson, P.; Udodong, U.; Fraser-Reid, B. J. Am. Chem.
Soc. 1988, 110, 5583-5584. (e) Fraser-Reid, B.; Wu, Z.; Udodong, U. E.;
Ottosson, H. J. Org. Chem. 1990, 55, 6068-6070. (f) Baeschlin, D. K.;
10.1021/ol034528v CCC: $25.00 © 2003 American Chemical Society
Published on Web 05/06/2003

group pattern on both donor and acceptor coupling partner,
and (3) can be employed in a one-pot glycosylation
procedure.
In Gin’s original dehydrative protocol, the 1-hydroxyl
donor 3 is condensed using an excess of acceptor 4b (1.5-
3.0 equiv) as well as activating agent 2a (1.4 equiv) to give
dimer 5b (Scheme 1). We anticipated that the presence of
excess 2a in our intended sequential strategy may lead to
unwanted activation of the thioglycoside 4a. It is also not
excluded12 that the excess of 2a can react with the free
hydroxyl group in acceptor 4a.13 It turned out that activation
of the incoming thioglycoside could be virtually suppressed
by the use of a slight excess of activator 2a (1.1 equiv) with
respect to the 1-hydroxyl donor, which in turn is employed
in excess to the thioglycosidic acceptor. For example,
activation of armed donor 8 (1.2 equiv) with Ph2SO/Tf2O in
the presence of TTBP (2,4,6-tri-tert-butylpyrimidine)14 and
condensation with the unreactive OH-4 of the armed thiogly-
cosiode 12 (1.0 equiv) gave thiodisaccharide 16 as an
anomeric mixture in excellent yield (Table 1, entry 1). It is
also of interest to note that disarmed donor 9 was efficiently
condensed under the same conditions with armed acceptor
13 to give ortho ester 17 in good yield (entry 2). Ortho ester
formation could also not be prevented15 in the condensation
of the pivaloylated glucose donor 10 and acceptor 13 (entry
2). On the other hand, the â-linked disaccharide 19 was
readily obtained by using an equimolar amount of base (entry
3). Finally, the potency of this procedure is illustrated by
the finding that furanosyl donor6b 11 could be used for the
condensation with both thio and selenoglycoside acceptors16
to afford the expected â-linked disaccharides 20 and 21,
respectively, in a satisfactory yield (entries 4 and 5).
We next turned our attention to the implementation of the
aforementioned coupling procedure in the synthesis of
biologically relevant trisaccharides. As a first example, we
focused on the R-Gal epitope, R-D-Gal-(1f3)-â-D-Gal-
(1f4)-â-D-GluNAc-OR, which is responsible for the antibody-
mediated hyperacute rejection in xenotransplantations.17 We
selected the fully protected R-Gal epitope 26,18 having an
azidopropyl spacer at the reducing end, as the target
compound (Scheme 2a). The glycosylation sequence com-
Figure 1. Sulfonium activator systems used for the activation of
1-hydroxyl and thiodonors.
armed and disarmed thiodonors are activated by 2b and
condensed with a highly disarmed thioglycoside. The result-
ing thiodisaccharide can now be activated by the relatively
more potent promotor 2a in the next glycosylation event.
Although this coupling sequence broadened the scope of
chemoselective glycosylations toward highly disarmed thiogly-
cosides, it is only applicable in assembly protocols using
donor glycosides in order of decreasing reactivity.9 Evidently,
glycosylation procedures that are independent of the reactiv-
ity of the donor building blocks would be more generally
applicable. We therefore turned our attention to the use of
1-hydroxyl donors, in combination with thiodonors, which
are both readily activated by sulfonium species 2a.10 We
reasoned that preactivation of hemiacetal donor 3 and
condensation with acceptor thioglycoside 4a would give the
thiodisaccharide 5a with the concomitant regeneration of
diphenylsulfoxide as a neutral side product (Scheme 1).6 In
Scheme 1. Sequential Glycosylation Strategy Using
1-Hydroxyl and Thiodonors
(11) For a sequential glycosylation procedure using trichloroacetimidates
and thioglycosides, see: (a) Yamada, H.; Harada, T.; Takahashi, T. J. Am.
Chem. Soc. 1994, 116, 7919-7920. (b) Yamada, H.; Harada, T.; Miyazaki,
H.; Takahashi, T. Tetrahedron Lett. 1994, 35, 3979-3982. (c) Yu, B.; Hui,
H.; Han, X. Tetrahedron Lett. 1999, 40, 8591-8594.
(12) The successful outcome of a condensation reaction, in which the
donor and acceptor are premixed before activation, is determined by the
relative nucleophilicities of the anomeric donor function, the anomeric
acceptor function, and the free hydroxyl group in the acceptor. See also
refs 5c and 13.
(13) Occurrence of this possibility is endorsed by the following experi-
ment: premixing the disarmed thiodonor ethyl 2,3,4,6-tetra-O-benzoyl-1-
thioglucopyranoside and the reactive acceptor R-O-methyl-2,3,4-tri-O-benzyl
glucose and subsequent treatment of this mixture with 1.0 equiv of the less
reactive 2b led to quantitative recovery of the donor glycoside and isolation
of the acceptor-6-O-benzenesulfinyl piperidine triflate adduct in 96% yield.
(14) Crich, D.; Smith, M.; Yao, Q.; Picione, J. Synthesis 2001, 323-
326.
(15) Although ortho ester formation rarely occurs when pivaloyl groups
are employed, it has been reported before: Plante, O. J.; Palmacci, E. R.;
Andrade, R. B.; Seeberger, P. H. J. Am. Chem. Soc. 2001, 123, 9545-
9554.
the subsequent 2a-mediated glycosylation, trisaccharide 7 can
then be constructed from thiodisaccharide 5a and terminal
building block 6. Herein we describe the development of
this novel glycosylation sequence combining 1-hydroxyl and
thio donors11 that (1) employs a single activator system, i.e.,
diphenylsulfide bis(triflate) 2a, (2) allows any protecting
(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) It was shown that the transiently formed (N-piperidino)phenyl(S-
thiophenyl)sulfide triflate, generated by the activation of an anomeric phenyl
thio function with BSP/Tf2O, could activate thioglycosides. See also ref
5c.
(10) BSP/Tf2O can also be used to activate 1-hydroxyl donors. Conden-
sation reactions using this activator system, however, require higher reaction
temperatures as compared to the Ph2SO/Tf2O-activated systems.
(16) Mehta, S.; Pinto, B. M. J. Org. Chem. 1993, 58, 3269-3276.
1948
Org. Lett., Vol. 5, No. 11, 2003

Table 1. Dehydrative Glycosylations Using 1-Hydroxyl Donors and Thioglycoside Acceptorsa
a Typically, the 1-hydroxyl donors (1.2-1.5 equiv with respect to the acceptor) were preactivated by Ph2SO (2.2 equiv with respect to the donor) and
Tf2O (1.1 equiv with respect to the donor) in the presence of TTBP (2.5 equiv with respect to the donor), followed by addition of the acceptor. b Anomeric
1
ratio determined from anomeric mixture by H NMR analysis. c Used 1.5 equiv of glycosyl donor. d TTBP was used in an equimolar amount with respect
to the donor glycoside.
mences with the diphenylsulfide bis(triflate) 2a-mediated
dehydrative condensation of the 1-hydroxyl galactose donor
22 and thiogalactose acceptor 23 to provide the R-linked
galactose dimer 24 as the sole product in 64% yield. In the
next coupling event, promotor 2a was employed to activate
the anomeric thio function in disaccharide 24. Reaction of
the activated dimer and the glucosamine building block 25
proceeded smoothly to afford target trisaccharide 26. With
these results in hand, we were anxious to find out whether
the assembly of trisaccharide 26 could also be attained in a
one-pot procedure (Scheme 2b). To this end, hemiacetal 22
was activated by Ph2SO/Tf2O and condensed with thio-
galactoside 23 leading to dimer 24 and the concomitant
regeneration of Ph2SO. At this stage, activation of intermedi-
ate 24 was effected by adding triflic anhydride to the reaction
mixture. Subsequent condensation with building block 25
led to the one-pot construction of the R-Gal epitope 26 in a
very rewarding yield of 80%.
A second touchstone for the developed sequential glyco-
sylation procedure was found in the synthesis of a hyaluronan
trisaccharide 31. Hyaluronan, involved in the regulation of
a variety of biological processes such as cell-cell recogni-
tion, cell migration, cell adhesion, and cellular proliferation,19
is a challenging synthetic target.20 In particular, the conden-
sation of highly disarmed glucuronic acid building blocks
such as 27 is notoriously difficult.21,22 Accordingly, the
synthesis of trisaccharide 31 was undertaken as outlined in
(17) (a) R-Gal and Anti-Gal in Subcellular Biochemistry; Galili, U.,
Avila, J. L., Eds.; Kluwer Academic/Plenum Publishers: New York, 1999;
Vol. 32. (b) Galili, U. Sci. Med. 1998, 5, 29-51. (c) Cooper, D. K. C.
Clin. Trans. 1992, 6, 178-183. (d) Cooper, D. K. C.; Good, A. H.; Koren,
E.; Oriol, R.; Malcolm, A. J.; Ippolito, R. M.; Neethling, F. A.; Ye, Y.;
Romano, E.; Zhudi, N. Transplant Immunol. 1993, 1, 198-205.
(18) For previous syntheses of the R-Gal epitope, see: (a) Garegg, P.;
Oscarson, S. Carbohydr. Res. 1985, 136, 207-213. (b) Schaubach, R.;
Hemberger, J.; Kinzy, U. Liebigs Ann. Chem. 1991, 607-614. (c) Reddy,
G. V.; Jain, R. K.; Bhatti, B. S.; Matta, K. L. Carbohydr. Res. 1994, 263,
67-77. (d) Vic, G.; Tran, C. H.; Scigelova, M.; Crout, D. H. G. Chem.
Commun. 1997, 167-170. (e) Nilsson, K. G. I. Tetrahedron Lett. 1997,
38, 133-136. (f) Fang, J.; Li, J.; Chen, X.; Zhang, X.; Wang, J.; Guo, Z.;
Zhang, W.; Yu, L.; Brew, K.; Wang, P. G. J. Am. Chem. Soc. 1998, 120,
6635-6638. (g) Hanessian, S.; Huynh, H. K.; Reddy, G. V.; Duthaler, R.
O.; Katopodis, A.; Streiff, M. B.; Kinzy, W.; Oehrlein, R. Tetrahedron 2001,
57, 3281-3290.
(19) Toole, B. P. Curr. Opin. Cel. Biol. 1990, 2, 839-844.
(20) For a recent review, see: (a) Yeung, B. K. S.; Chong, P. Y. C.;
Petillo, P. A. J. Carbohydr. Chem. 2002, 21, 799-865. (b) Glycochemis-
try: Principles, Synthesis, and Applications; Wang, P. G., Bertozzi, C. R.,
Eds.; Marcel Dekker: New York, 2001; pp 425-492.
(21) Garegg, P. J.; Olsson, L.; Oscarson, S. J. Org. Chem. 1995, 60,
2200-2204.
Org. Lett., Vol. 5, No. 11, 2003
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Scheme 2. Synthesis of the R-Gal Epitopea
Scheme 3. Synthesis of a Hyaluronan Trisaccharidea
a Key: (a) 27 (1.5 equiv), Ph2SO, Tf2O, TTBP (1.5 equiv), -60
to -15 °C, 1 h, then 28, -15 °C to rt. (b) Ph2SO, Tf2O, TTBP,
-60 °C, 10 min, then 30, -60 to 0 °C.
a Key: (a) 22 (1.2 equiv), Ph2SO, Tf2O, TTBP, -60 to -40 °C,
1 h, then 23, -40 to 0 °C. (b) Ph2SO, Tf2O, TTBP, -60 °C, 10
min, then 25, -60 to 0 °C.
is independent of the protecting groups in the carbohydrate
building blocks. The scope of the strategy was further
broadened by the development of a novel one-pot glycosy-
lation protocol, which has been used for the construction of
two biologically relevant trisaccharides. With the ultimate
goal of developing efficient sequential synthesis strategies
for the assembly of more complex oligosaccharides, research
is currently underway to extend the developed methodology
using different seleno- and thioglycosides and other sulfo-
nium activator systems.
Scheme 3a. Thus, glucuronic acid 27 was activated with 2a
and coupled to ethylthio N-phthaloyl glucosamine 28 to
afford the â-disaccharide 29 in a satisfactory 58% yield.
Consecutive coupling of 29 with glucuronic acid building
block 30 completed the synthesis of the protected hyaluronan
trisaccharide 31. Executing the same set of reactions in the
one-pot protocol as depicted in Scheme 3b led to the isolation
of the target compound in a comparable yield (32%).
In conclusion, 1-hydroxyl donors can efficiently be
condensed with thioglycosides under the action of diphen-
ylsulfide bis(triflate) 2a. The resulting thiodisaccharides can
be further elongated in the next glycosylation step using the
same promotor system. This novel condensation sequence
Acknowledgment. We thank the Council for Chemical
Sciences of The Netherlands Organization for Scientific
Research (CW-NWO), The Netherlands Technology Foun-
dation (STW), and Organon N.V. for financial support.
Supporting Information Available: General coupling
procedures and characterizations of all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(22) Several syntheses of hyaluronan oligosaccharides avoid the use of
glucuronic acid building blocks for this reason. Alternatively, glucopyranose
building blocks are employed that are orthogonally protected on the
6-position, which after deprotection is oxidized at the end of the synthesis.
See ref 20.
OL034528V
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Org. Lett., Vol. 5, No. 11, 2003