carbohydrate synthesis are much less effective,10 which is even
more so for the two-phase reactions in solid-phase synthesis.
Consequently, after a few steps of glycosylations, a significant
amount of side products with deficient carbohydrate sequences
will accumulate on the resin, whereas only a low yield of the
desired oligosaccharide will be formed. After the products are
released from the resin, the desired oligosaccharide has to be
isolated from a large quantity of impurities, which can be
especially challenging. Meanwhile, the removal of an array of
side products that are different by just one sugar unit is another
notable difficulty.11 Therefore, an efficient method to purify the
desired final product is one of the key issues that needs to be
addressed to achieve practical, automated solid-phase carbohy-
drate synthesis.
Cap and Capture-Release Techniques Applied to
Solid-Phase Synthesis of Oligosaccharides
Jian Wu and Zhongwu Guo*
Department of Chemistry, Wayne State UniVersity,
5101 Cass AVenue, Detroit, Michigan 48202
ReceiVed February 7, 2006
In recent years, many new and interesting strategies have been
developed for product isolation and purification in organic
synthesis,12,13 among which the capture-release technique using
various unique “capture” reagents has been extensively inves-
tigated in combinatorial, solution-phase, and solid-phase syn-
thesis of peptides, carbohydrates, and other molecules.14,15 The
basic principle of this strategy is to label the desired product
with a tag during the synthetic process. After the synthesis is
finished, the tagged structures are captured by materials, such
as resin or column, which can specifically bind or react with
the tag to facilitate the separation of the desired products.
Insoluble polymers are commonly used as capture materials,
as they enable separation by filtration.
The polymer-based capture-release technique has brought
up many brilliant designs for carbohydrate synthesis.15 For
example, in soluble polymer-supported carbohydrate synthesis,
Ito and co-workers10,16,17 used the chloroacetyl (ClAc) group
as a temporary protection of hydroxyl groups and as the tag for
solid-phase capture-release as well. After each glycosylation
reaction, the product was treated with a capture resin having
free thio groups. Although the unreacted glycosyl acceptor was
inert to capture resin, the elongated sugar chains, which
contained ClAc, would link to the resin via the thio groups.
The loaded resin could be easily separated from the side products
by filtration. Thereafter, the oligosaccharide on the capture resin
was released and then subjected to the next cycle of polymer-
supported reaction and capture-release purification. A useful
feature of this approach is that each glycosylation product was
purified. Another elegant approach was developed by Fukase
and co-workers18,19 using 3-chloro-4-azidobenzyl (ClAzb) as a
temporary protecting group and the tag of incoming sugar units.
After the elongation was completed and the carbohydrates were
detached from the solid-phase support, the desired oligo-
This paper reports a new strategy for oligosaccharide
synthesis by combining solid-phase methods with cap and
capture-release separation techniques, using the p-(5-
(ethoxycarbonyl)pentyloxy)benzyl group (CPB) as a tag for
the capture of desired oligosaccharides. After a complex
carbohydrate mixture was obtained by solid-phase synthesis,
the desired oligosaccharide containing a free carboxyl group
derived from CPB was attached to an amino resin. The
loaded resin was readily separated from side products by
filtration and finally treated with acid to release the pure
oligosaccharide product.
Among the three major classes of biooligomers, which include
oligosaccharides, oligonucleotides, and oligopeptides, the struc-
ture of oligosaccharides is by far the most complex and diverse.
As a result, the chemical synthesis of oligosaccharides posts
an important challenge in organic chemistry,1 despite the
significant advancement in carbohydrate chemistry in the past
three decades.2-5 For instance, although automated solid-phase
synthesis of oligonucleotides and oligopeptides using synthesiz-
ers has become routine, the attempt to automate solid-phase
oligosaccharide synthesis has just started.6 Solid-phase carbo-
hydrate synthesis has shown great promise,7-9 as it can
significantly simplify the oligosaccharide assembly by eliminat-
ing the time-consuming process of intermediate purification.
However, it is exactly this feature that often complicates the
final product purification.
(10) Ando, H.; Manabe, S.; Nakahara, Y.; Ito, Y. Angew. Chem., Int.
Ed. 2001, 40, 4725.
Compared to the coupling reactions used in peptide and
nucleotide synthesis, glycosylation reactions established for
(11) Palmacci, E. R.; Hewitt, M. C.; Seeberger, P. H. Angew. Chem.,
Int. Ed. 2001, 40, 4433.
(12) Curran, D. P. Angew. Chem., Int. Ed. 1998, 37, 1174.
(13) Tzschucke, C. C.; Markert, C.; Bannwarth, W.; Roller, S.; Hebel,
A.; Haag, R. Angew. Chem., Int. Ed. 2002, 41, 3964.
(14) Kirschning, A.; Monenschein, H.; Wittenberg, R. Chem.-Eur. J.
2000, 6, 4445.
(15) Ito, Y.; Manabe, S. Chem.-Eur. J. 2002, 8, 3076.
(16) Hanashima, S.; Manabe, S.; Ito, Y. Synlett 2003, 979.
(17) Hanashima, S.; Manabe, S.; Ito, Y. Angew. Chem., Int. Ed. 2005,
44, 4218.
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(3) Koeller, K. M.; Wong, C.-H. Chem. ReV. 2000, 100, 4465.
(4) Demchenko, A. V. Synlett 2003, 1225.
(5) Boons, G.-J. Tetrahedron 1996, 54, 1095.
(6) Plante, O. J.; Palmacci, E. R.; Seeberger, P. H. Science 2001, 1523.
(7) Seeberger, P. H.; Danishefsky, S. J. Acc. Chem. Res. 1998, 31, 685.
(8) Seeberger, P. H.; Haase, W.-C. Chem. ReV. 2000, 100, 4349.
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(18) Egusa, K.; Kusumoto, S.; Fukase, K. Synlett 2001, 777-780.
(19) Egusa, K.; Kusumoto, S.; Fukase, K. Eur. J. Org. Chem. 2003, 3435.
10.1021/jo060255g CCC: $33.50 © 2006 American Chemical Society
Published on Web 07/29/2006
J. Org. Chem. 2006, 71, 7067-7070
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