An iterative route to "decorated" ethylene glycol-based linkers

Article abstract of DOI:10.1039/b518061a

Iterative copper-catalyzed cycloadditions of azides to alkynes were used to join functionalized triethylene glycol molecules to give "linkers" of defined lengths equipped with several different end-group functionalities. The Royal Society of Chemistry 200

Full text of DOI:10.1039/b518061a

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An iterative route to ‘‘decorated’’ ethylene glycol-based linkers{
Genliang Lu, Sang Lam and Kevin Burgess*
Received (in Austin, TX, USA) 20th December 2005, Accepted 13th February 2006
First published as an Advance Article on the web 7th March 2006
DOI: 10.1039/b518061a
Iterative copper-catalyzed cycloadditions of azides to alkynes
were used to join functionalized triethylene glycol molecules to
give ‘‘linkers’’ of defined lengths equipped with several different
end-group functionalities.
Oligomeric compounds of a perfectly defined length, polydispersity
1.0, are highly desirable for a variety of applications. We were
interested in using them to link peptidomimetics providing bi- and
multivalent molecules that might potentially bind with protein
targets.1 We needed linkers with some intrinsic water solubility,
that did not have charged functional groups, but that were able to
˚
˚
span dimensions from about 10 A to around 50 A. They might
also incorporate heterocyclic functionality that could interact with
the protein in some positive way. Further, they should be
functionalized with end groups that allow pharmacophores or
other groups of interest to be attached.
The literature reveals only a few potential leads to the linker
types described above. Purified polyethylene glycols are unsuitable
because they are mixtures of compounds having different
molecular masses. Oligoethylene glycol units of defined length
can be made,2–4 but even the best methods require long reaction
times and several chromatographic separations. In fact, routes that
feature iterative SN2 ether-bond-forming steps are vulnerable to
formation of vinyl ether side-products via competing elimination
reactions. If these were not removed then acid treatment would
give products with only one ethylene glycol unit less.
Accumulation of these deletion products would be hard to
separate after multiple steps, hence chromatography was required
after every iteration. Oligomers that incorporate guanidine and
ethylene glycol fragments also have been made,5 but these may be
too polar for some applications.
Fig. 1 Approach to functionalized oligomers of defined length.
(Aldrich), via the tosylate 2 in the three steps shown below
(Scheme 1). Others using this methodology would probably
modify the end-group structure according to their specific needs.
Molecules B (Fig. 1) are used repeatedly in the propagation
steps, hence clean, concise, synthetic access to this fragment was
highly desirable. The alkyne-tosylate 3 was selected as this pivotal
intermediate. It was formed by tosylation of the corresponding
alcohol 4. Previous syntheses of alcohol 4 involved monosilation,
alkylation, and desilation steps,11 but here it was realized that
selective monoalkylation of triethylene glycol was possible, under
conditions that do not involve toxic or expensive reagents. Thus
the approach to the alkyne-tosylate 3 in Scheme 2 is direct and
convenient.
Fig. 1 outlines the central concept for this communication. A
functionalized azidoethylene glycol unit A is reacted with a
propargylated ethylene glycol tosylate B via a copper-catalyzed 2 +
3 cycloaddition.6–8 Displacement of the tosylate with azide and
reaction with another equivalent of monomer B allows for
controlled, stepwise chain-growth. Finally, the chain is capped
by addition of an appropriate end-group. This is a novel approach
to linkers of a defined length. A conceptually similar iterative
approach to expanding dendrimers was published while this work
was in progress.9
Scheme 3 outlines the iterative sequence used to prepare the
linkers. In these experiments, a slight excess of the core synthon 3
was used, and the yields shown were based on the azide
components after chromatographic purification following each
A phthalyl-triethylene glycol 110 was selected to prepare linker
with protected amine functionalities (corresponds to unit A in the
Fig. 1). It was made from a commercially available chloroalcohol
Texas A&M University, Chemistry Department, P.O. Box 30012,
College Station, Texas, 77842, USA. E-mail: burgess@tamu.edu;
Fax: +1 979 845 4345; Tel: +1 979 845 8839
{ Electronic supplementary information (ESI) available: Experimental
section. See DOI: 10.1039/b518061a
Scheme 1 Synthesis of the end-group unit 1.
1652 | Chem. Commun., 2006, 1652–1654
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Scheme 2 Synthesis of the key component for iterative chain elongation.
cycloaddition. HPLC analyses gave no indication of elimination
by-products in the azide displacement steps, and the chromato-
graphic separations were straightforward.
Scheme 4 Synthesis of an oligomer without purification of intermediates.
particularly useful since almost any functionalized terminal alkyne
can be added via copper-catalyzed cycloadditions. Thus, Fig. 2b
features combination of the alkyne-ester 12 (from alkylation of
alcohol 4 with tert-butyl bromoacetate) and the azide 6 to give the
system 13. The latter reaction is more convergent than the first
because it introduces another triethylene glycol unit with the
It was desirable to prove that multiple chromatographic
separations were not essential in the sequence above. Columns
were performed to obtain material for characterization, but the
reactions are relatively clean. Consequently, it was decided to
attempt the whole process using just one chromatographic
separation in the closing stage (Scheme 4). In this case
stoichiometric amounts of the azide 1 and the alkyne 3 were used.
Water was added after each reaction, and the desired materials
were extracted back into dichloromethane. Finally, the tosylate 9
was easily purified via flash chromatography, and pure material
was obtained in 39% overall yield.
Both the tosylate and azide intermediates in the linker syntheses
could be functionalized to give many different types of linkers. We
were most interested in mono-protected diamines and protected-
amino acids. Consequently, three reactions were performed
(Fig. 2). In the first (Fig. 2a), the tosylate 5 was reacted with
Boc-protected piperazine to give the differentially protected
diamine 11. Azide intermediates in the linker syntheses are
Fig. 2 Elaboration of the core linker fragments via: a reaction of a
tosylate; b ‘‘click’’ reaction of another triethylene glycol-derived alkyne;
and, c combination with a different terminal alkyne.
Scheme 3 Iterative chain-elongation.
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basic (the pKa of the protonated form of 1-N-methyltriazole is less
than 2.0),13 but they may have some characteristics that might be
exploited. For instance, it seems likely that they might be able to
form non-covalent interactions with proteins. It also would be
intriguing to ascertain how they might complex with metals, both
in a controlled environment and under physiological conditions.
Finally, potential pharmaceuticals developed using linkers of
perfectly defined length tend to be easier to steer through the
regulatory process surrounding clinical trials and government
approval than similar, but non-homogeneous, systems; this could
be a major advantage of the linkers described here.
Financial support for this project was provided by the National
Institutes of Health (CA82642 and GM076261), and the Robert A.
Welch Foundation. TAMU/LBMS-Applications Laboratory
headed by Dr Shane Tichy provided mass spectrometric support.
The NMR instrumentation in the Biomolecular NMR Laboratory
at Texas A&M University was supported by a grant from the
National Science Foundation (DBI-9970232) and the Texas A&M
University System.
Fig. 3 Lengths of various linker molecules in completely extended
Notes and references
conformations.
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Tetrahedron Lett., 2004, 45, 4285. Bifunctional oligoethylene glycol units
of 12- and 24-ethylene glycol units are commercially available (Quanta
Biodesign).
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second end-group. Finally, azide 10 was joined with 1-heptynoic
acid (Fig. 2c).
Illustrative linker molecules in completely extended conforma-
tions were modeled to visualize their relative lengths (Fig. 3). On
this basis, terminal O-atoms in triethylene glycol are separated by
˚
approximately 11 A. Insertion of a triazole-methylene fragment
˚
into a chain seems to elongate it by around 4.5 A, though this is
approximate since the completely extended conformation is not
linear like it is for a hydrocarbon. Nevertheless the maximum span
of the linkers may be estimated using these dimensions of the
building blocks.
6 H. C. Kolb, M. G. Finn and K. B. Sharpless, Angew. Chem., Int. Ed.,
2001, 40, 2004.
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Described here is a means to form linear oligoethylene glycol-
based linkers of perfectly defined lengths. They were functionalized
by several end-groups, and it is clear that many others could be
used to design oligomers for other purposes. There is also scope for
variation of the oligoethylene glycol units; indeed, we have already
made similar systems based on hexaethylene glycol.12 The linkers
are easily made in an iterative process. We suspect it might be
possible to automate the steps in the synthesis leading to the
chromatographic separation, since the work-up at each stage only
involves organic/aqueous separations. The triazole units incorpo-
rated into these linkers differentiate them from oligo- or
polyethylene glycols. They do not make the systems significantly
1654 | Chem. Commun., 2006, 1652–1654
This journal is ß The Royal Society of Chemistry 2006