(ethylene glycol) synthesis.4 On the other hand, monoprotection
and monofunctionalization of oligo(ethylene glycol) are quite
important procedures for use of oligo(ethylene glycol) as a
building compound. Recently, a general synthetic procedure for
bifunctional oligo(ethylene glycol) toward 24-mer has been
reported,5 where monoprotection and monofunctionalization of
oligo(ethylene glycol) are achieved by using silver(I) oxide6
without employing an excess amount of oligo(ethylene glycol).7
This procedure is of great interest; however, there might be room
to improve the procedure for longer oligo(ethylene glycol)
synthesis, and nonsymmetrical (described in this procedure5)
and symmetrical oligo(ethylene glycol) syntheses are comple-
mentary to each other. This context prompted us to investigate
synthesis of oligo(ethylene glycol) by using commercially easily
available materials with simple procedures, especially in
purification, as much as possible.
Synthesis of Oligo(ethylene glycol) toward 44-mer
Saleh A. Ahmed† and Mutsuo Tanaka*
Institute for Biological Resources and Functions, AIST,
Central 5, 1-1-1, Higashi, Tsukuba, Ibaraki 305-8565, Japan
ReceiVed August 23, 2006
As a fundamental synthetic method, we adopted Williamson’s
ether synthesis where elimination reaction is the most significant
side reaction. Two synthetic routes were evaluated as shown in
Scheme 1, where PG, OEG, and X represent protecting group,
oligo(ethylene glycol), and functional group, respectively. In
route 1, excess addition of functionalized monoprotected oligo-
(ethylene glycol), PG-OEG1-X, might give better yield against
the elimination reaction, and GPC (gel-permeation chromatog-
raphy) separation of the product and byproducts seems to be
easier as the byproducts derived from elimination reaction of
PG-OEG1-X may be much different from the product in
molecular weight. To the contrary, the elimination reaction is
fatal in route 2, and byproducts derived from elimination
reaction of the intermediate, PG-OEG1-OEG2-X, could have
heavier molecular weights that result in difficulty in GPC
separation. In order to reduce influence of the elimination
reaction as much as possible, therefore, route 1 was considered
to be more suitable than route 2.
First, synthesis of dodeca(ethylene glycol) was examined as
a prototype. Monoprotection of tetra(ethylene glycol) was carried
out with various common protecting groups as shown in Scheme
2 (step a). With purification at the final step taken into account,
benzyl, tetrahydropyranyl, and trityl groups were nominated as
protecting groups. After deprotection of those protecting groups,
simple procedures such as filtration, solvent evaporation, and
solvent extraction are anticipated to give the desired oligo-
(ethylene glycol) in sufficient purity. All reactions gave suf-
ficient results with small amount of diprotected tetra(ethylene
glycol)s by using excess amount of tetra(ethylene glycol), where
the excess tetra(ethylene glycol) was easily removed during
solvent extraction with chloroform. The obtained crude products
were used for subsequent reactions without further purification.
At step b in Scheme 2, tosylation, mesylation, and chlorina-
tion were evaluated to functionalize monoprotected tetra-
A synthetic method for oligo(ethylene glycol) toward 44-
mer (FW ) 1956.35) is described. Reiteration of William-
son’s ether synthesis and hydrogenation to remove protecting
benzyl group affords desired oligo(ethylene glycol) toward
44-mer in moderate yields. The advantages in this method
are use of commercially easily available materials as starting
materials and procedures avoiding difficulty in purification
of the products as much as possible.
Recently, oligo(ethylene glycol) has been a fascinating
building compound because of flexibility, chemical stability,
water solubility, nontoxicity, property of suppressing nonspecific
interaction with protein, and so on.1 Especially, the property of
suppressing nonspecific interaction with protein makes oligo-
(ethylene glycol) a promising biocompatible material to compose
not only various bioactive compounds but also medical analysis
devices.2 Although oligo(ethylene glycol)s below 6-mers and
poly(ethylene glycol)s3 with narrow molecular weight distribu-
tions above 2000 molecular weight are commercially available,
monodisperse oligo(ethylene glycol)s between 7-mers and 2000
molecular weight are not commercially available; otherwise they
are quite expensive and beyond use as starting materials. To
the best of our knowledge, a general procedure to synthesize
oligo(ethylene glycol) around 2000 molecular weight has not
been reported, although there are a few reports including oligo-
† Present address: Chemistry Department, Faculty of Science, Assiut
University, 71516 Assiut, Egypt.
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and Biomedical Applications; ACS Symposium Series 680; American
Chemical Society: Washington, DC, 1997. (c) Dickerson, T. J.; Reed, N.
N.; Janda, K. D. Chem. ReV. 2002, 102, 3325-3343.
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D. Macromolecules 2005, 38, 10609-10613.
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2001, 42, 3819-3822. (d) Chen, Y.; Baker, G. L. J. Org. Chem. 1999, 64,
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10.1021/jo0617464 CCC: $33.50 © 2006 American Chemical Society
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