Carboaminoxylation as a tool to prepare functionalized polymeric materials: Introduction of biologically important residues by metal-free radical C-C coupling reactions

Article abstract of DOI:10.1002/chem.201003163

Making a radical change! Radical C-C bond formation by thermal carboaminoxylation of alkoxyamines was used for functionalization of unsaturated macromolecular systems with biologically important residues (R; see scheme). The synthesized dendritic mannose-containing glycopolymers show very strong inhibition of the lectin Concanavalin A as measured by an enzyme-linked lectin assay. Copyright

Full text of DOI:10.1002/chem.201003163

DOI: 10.1002/chem.201003163
Carboaminoxylation as a Tool to Prepare Functionalized Polymeric
Materials: Introduction of Biologically Important Residues by Metal-Free
À
Radical C C Coupling Reactions
Jean-Pierre Lindner and Armido Studer*[a]
One of the fundamental goals in chemical and biological
research is the understanding of complex biological interac-
tions like cellular communication processes or immune re-
sponse. For biological interactions, multivalency plays an im-
portant role.[1] A well-known example is the glycoside clus-
Scheme 1. Carboaminoxylation of an olefin with an alkoxyamine.
ter effect, in which multivalent carbohydrate ligands bind
stronger to their corresponding receptors than the monova-
lent counterparts on a saccharide-per-mol basis.[2] Unfortu-
nately, it is very difficult to study in vivo single interactions
between a ligand (for example, a carbohydrate or a small
peptide) and a receptor on the cell surface. To circumvent
this problem, cell-surface surrogates have been prepared,
which exhibit only a certain type of ligand or receptor.
These surrogates not only simplify studies of ligand receptor
interactions, but they can also be tuned to exceed the affini-
ty of a natural substrate, which facilitates their use in medi-
cal applications.[3] Known examples are glycopolymers,
which have been successfully prepared and used to study
binding behavior with lectins and other protein receptors.[4]
To synthesize such cell surface surrogates, easy accessible
building blocks like polymers have been used. To introduce
the relevant structures onto the polymeric scaffolds, two dif-
ferent approaches have been followed. One is to first syn-
thesize monomers containing the requested functional
moiety which are then polymerized to give the targeted
hybrid polymers.[5] The other route uses readily available
polymers that contain reactive side chains at the backbone
(for example olefins) that are used for conjugation of bio-
logically interesting moieties.[6]
Importantly, no initiator or catalyst has to be added to
conduct the carboaminoxylation reaction. This reaction has
been successfully applied to the chemical modification of
various olefins.[8] Even surface radical carboaminoxylation is
possible,[9] although the efficiency of such a reaction de-
pends on the nitroxide structure. It was recently shown by
our group that alkoxyamines 3 substituted with a nitroxide
4, (which is easy accessible on a large scale), show high effi-
ciency in carboaminoxylation reactions.[8k] Herein, we report
the application of radical carboaminoxylation of alkoxya-
mines 3, functionalized with biologically relevant moieties,
with a test substrate 1-octene and with macromolecules con-
taining multiple double bonds. Moreover, we will show that
this approach can be used for the synthesis of strong lectin
binders.
Alkoxyamines have been applied as precursors for C-cen-
tered radicals that react readily with unactivated double
bonds.[7] In so called carboaminoxylation reactions, thermal
À
homolytic C O bond cleavage of an alkoxyamine 1 gener-
ates a transient C-centered radical and a persistent nitroxide
radical. C-radical addition onto the olefin and trapping of
the adduct radical with the nitroxide provides product 2
(Scheme 1).
We first synthesized alkoxyamines 3a–3e containing bio-
logically interesting moieties (see the Supporting Informa-
tion for details). As a test reaction, the carboaminoxylation
of 1-octene was studied and the results are summarized in
Scheme 2. The best results were achieved by performing the
reaction in dichloroethane (DCE) at 1258C for 4 h. Addi-
tion of the dansyl alkoxyamine 3a to 1-octene provided
product 5a in a good yield (83%). Addition of the hydro-
phobic tripeptide 3b occurred near quantitatively (97%). It
is important to note that the free hydroxyl groups showed
no detrimental effect on the addition reaction, as shown for
reactions with alkoxyamines 3c–3e (Scheme 2). Carboami-
[a] J.-P. Lindner, Prof. Dr. A. Studer
Organisch-Chemisches Institut
Westfꢀlische Wilhelms-Universitꢀt Mꢁnster
Corrensstrasse 40, 48149 Mꢁnster (Germany)
Fax : (+49)251-8336523
E-mail: studer@uni-muenster.de
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201003163.
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Chem. Eur. J. 2011, 17, 4090 – 4094

COMMUNICATION
found that the addition of dansyl alkoxyamine 3a to 6 af-
forded the corresponding dye-loaded polyalkoxyamine 8a
with a degree of functionalization of 39% (Scheme 3). Car-
boaminoxylation of 6 with peptide-containing alkoxyamine
3b showed a higher conversion of the terminal olefins (54%
functionalization). By using the alkoxyamines 3c–3e, which
are modified with unprotected sugar residues, lower degrees
of functionalization of 43, 44, and 32% were achieved
(Scheme 3).
Scheme 2. Carboaminoxylation of 1-octene with alkoxyamines 3a–3e;
DCE=dichloroethane, Boc=tert-butoxycarbonyl, Bn=benzyl.
noxylation of 3c to 1-octene gave the addition product 5c in
a very high yield (94%). We also tested the temperature de-
pendence of the carboaminoxylation by using the addition
of 3c to 1-octene as a representative example. At 100 and
808C for 4 h, the yields significantly decreased to 40 and
22%, respectively, however, at 608C the reaction did not
occur. These results suggest that at temperatures below
1258C, the equilibrium between the dormant alkoxyamine
and the reactive malonyl radical lies too far on the non reac-
tive alkoxyamine side. Therefore, the following experiments
were conducted at 1258C (Scheme 2). By using the estab-
lished protocol, the addition of alkoxyamines 3d–3e to 1-
octene gave the corresponding adducts 5d–5e in excellent
yields (92%). Both ester moieties of the malonate can be
charged with biologically interesting residues, as shown in
the carboaminoxylation with 3e that contains 8 free OH
groups (Scheme 2).
Scheme 3. Chemical functionalization of poly(butadiene) 6.
We then decided to apply our radical addition reaction to
the modification of perallylated polyglycerol 7 (Scheme 4).
Experiments were conducted in the same manner to those
performed with 1-octene and 6. Scheme 4 depicts the results
obtained for carboaminoxylations of 7 with 3a–3e.
Addition of 3a to 7 gave 9a with approximately 40%
degree of functionalization, whereas peptide 3b was incor-
porated to give 9b in 26% yield (Scheme 4). Reaction of 7
with the carbohydrate residues bearing alkoxyamines 3c,
3d, and 3e gave, in one step, dendritic glycopolymers 9c–
9e, with 44, 54, and 30% functionalization, respectively
(Scheme 4).[12] Given that approximately 84 allylic moieties
per polyglycerol are available for conversion (as analyzed
Encouraged by these results we focused on the functional-
ization of more interesting systems, that is, macromolecules
containing multiple double bonds for preparation of func-
tionalized macromolecules. The chemical modification of
polymers by using click-type chemistry has recently gained
increased attention.[6a–e,10] Towards this end, we chose poly-
1
(butadiene)
6
(Mn =1800 gmolÀ1, polydispersity index
by H NMR spectroscopy, see the Supporting Information),
(PDI)=1.34, according to 1H NMR data: ratio 1,2 vs. 1,4 ad-
dition=1.8:1) and perallylated polyglycerol 7, which is read-
ily prepared from commercially available polyglycerol (Mn =
6000 gmolÀ1, (PDI)<1.5).[11] Reactions were conducted
under the optimized conditions described above (DCE,
1258C, 4 h). Carboaminoxylation of poly(butadiene) 6 re-
vealed that preferentially terminal double bonds reacted
with the alkoxyamines for steric reasons (Scheme 3). The
poly(butadiene) addition products were purified by dialysis
(see the Supporting Information for details). The product
the actual number of attached carbohydrate moieties is ap-
proximately 37 for 9c, 45 for 9d, and 50 for 9e. In contrast
to polymer 9e, glycopolymers 9c and 9d were not soluble in
water, although all polymers contain quite a large number
of immobilized hydrophilic carbohydrate moieties. This solu-
bility behavior is probably caused by the hydrophobic al-
koxyamine residues attached to the polymer backbone,
which is supported by the fact that the number of attached
alkoxyamines is significantly higher in polymers 9c and 9d
than in polymer 9e (Scheme 4).
1
was then analyzed by using H NMR spectroscopy to deter-
The lower yields observed for carboaminoxylation of
polymers 6 and 7, as compared with the functionalization of
the model olefin 1-octene, is probably caused by the limited
access of the malonyl radicals to the olefins at higher de-
mine the ratio of unreacted terminal olefinic protons to
characteristic protons of the conjugated alkoxyamine (for
1H NMR spectra, see the Supporting Information). We
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A. Studer and J.-P. Lindner
Scheme 5. Iterative double and triple functionalization of perallylated
polyglycerol 7.
Scheme 4. Chemical functionalization of perallylated polyglycerol 7.
grees of functionalization. The introduced functionalities
hinder the approach of carbon radicals to the olefinic ac-
ceptors. Additionally, decomposition of the alkoxyamine
by the first two carboaminoxylations. The overall degree of
functionalization for the polymer was 46%.
A double functionalization of 7 was also performed with
mannose and glucose derivatives 3c and 3d to afford the
mixed dendritic glycopolymer 12 with a ratio of glucose/
mannose of nearly 1:1 and an overall degree of functionali-
zation of 51% (Scheme 6). By using this straightforward
one-pot procedure, mixed glycoclusters could be obtained
without the use of any transition-metal catalyst or initiator.
À
substrate can occur by an ionic fragmentation pathway (N
O bond cleavage), via the enol tautomer of the malonic
ester moiety, leading to consumption of the starting alkoxya-
mine. We tried to improve the yield of the carboaminoxyla-
tion of 7 by increasing the amount of alkoxyamine, however
the degree of functionalization could not be improved.
To further extend the scope of this approach, we decided
to conduct polyfunctionalizations by using 7 as the substrate
(Scheme 5). Double functionalization could be achieved in
an iterative process. To this end, compound 7 was first car-
boaminoxylated with alkoxyamine 3a and subsequently with
3b to give the product 10, a dansyl- and peptide-containing
polyglycerol with 51% overall conversion of the allylic
double bonds (Scheme 5). The ratio of dye versus peptide
1
was approximately 0.86:1, as analyzed by H NMR spectros-
copy. Also a triple iterative functionalization of perallylated
polyglycerol 7 was achieved to give multifunctionalized pol-
yglycerol 11 (Scheme 5). The reaction was conducted in
analogy to the double functionalization with iterative car-
boaminoxylations using 3a, 3b, and 3c. Purification of 11
was conducted by dialysis. The ratio of dye/peptide/carbohy-
drate in the multifunctional polymer was 0.8:1.0:0.5, as de-
termined by 1H NMR spectroscopy. The lower degree of
functionalization for the last incorporated residue is most
likely due to the enhanced steric hindrance, which is caused
Scheme 6. One-pot carboaminoxylation of 7 with 3c and 3d.
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Carboaminoxylation as a Tool to Prepare Functionalized Polymeric Materials
COMMUNICATION
To show that the obtained polymer hybrids are suitable
soft materials to study biological interactions, we tested the
binding of the water-soluble dendritic glycopolymer 9e in-
corporating around 50 mannose moieties with the lectin
Concanavalin A (Con A). It is known that this lectin specifi-
cally binds a-mannose and b-glucose moieties, and due to
the glycoside cluster effect, the binding affinity to a lectin
dramatically increases upon interaction with a multivalent
sugar-containing ligand.[2a,13] To prove the lectin recognition
ability of 9e, we conducted a turbidimetric assay to measure
the changes in absorbance at a wavelength of 400 nm during
the interaction of glycoplymer 9e with Con A.[5c,14] Solutions
containing only Con A or only glycopolymer 9e remained
clear. However, instantaneous precipitation occurred after
addition of the glycopolymer 9e to a solution of Con A
(Figure 1, see the Supporting Information for details).
and a-d-methylmannose as a reference soluble ligand. We
determined the IC50 values of the dimannose ligand 5e, and
glycopolymers 9e containing 32 (9e32) and 50 (9e50) man-
nose residues. The assays were carried out by standard pro-
tocols according to the literature (details can be found in
the Supporting Information).[15] Table 1 shows the results of
these measurements.
Table 1. IC50 values and relative potencies of a-d-methylmannose, 5e,
9e32, and 9e50.
Compound
IC50 [nm]
IC50 per
saccharide [nm]
Relative
potency
a-d-methylmannose
dimannose ligand 5e
glycopolymer 9e32
glycopolymer 9e50
1ꢃ106
0.6ꢃ106
3.6
1ꢃ106
1.2ꢃ106
115
1
0.8
8.7ꢃ103
5ꢃ104
0.4
20
The IC50 value for a-d-methylmannose was about 1 mm,
which is in agreement with previously reported results.[15]
The IC50 values obtained for the ligands 5e, 9e32, and 9e50
were 0.6 mm, 3.6 nm, and 0.4 nm, respectively (Table 1). The
last two values are several orders of magnitude below the
mannose reference. Considering the numbers of mannose
residues in each ligand, the IC50 values per sugar residue are
1.2ꢃ106, 115, and 20 nm, respectively; this means an en-
hancement of the binding activity on a per carbohydrate
basis of 0.8, 8.7ꢃ103, and 5ꢃ104 for 5e, 9e32, and 9e50, re-
spectively (Table 1). Glycopolymer 9e50 is one of the stron-
gest known inhibitors of Con A. The relative potencies
clearly show the multivalent binding of the soluble ligands
9e to the lectin, which is illustrated by the nonlinear in-
crease in relative potencies of the binding activities of the
mannose residues. The massive increase in binding activity
can be explained by the glycoside cluster effect; the increase
of binding activity is a result of multivalent interactions be-
tween the polyvalent sugar ligand and an appropriate recep-
tor.[2]
In conclusion, the carboaminoxylation of 1-octene, poly-
butadiene 6, and perallylated polyglycerol 7 was successfully
performed with alkoxyamines, substituted with biologically
interesting moieties. Yields were good (for polymers) to ex-
cellent (for octene). Polyfunctionalization could also be ach-
ieved by iterative carboaminoxylation of up to three differ-
ent alkoxyamines. It was shown that the polymer hybrids
obtained by this method are interesting for studying biologi-
cal interactions. This was proved by studying the interaction
of glycopolymer 9e with lectin Con A, which was analyzed
by a turbidimetric and an enzyme-linked lectin assay. The
latter revealed a very low IC50 value for 9e50 of about
0.4 nm, revealing that 9e50 is a very strong Con A inhibitor.
Figure 1. Turbidimetric assay of 9e with Con A at
a
wavelength of
400 nm: =Con A (1 mgmLÀ1), 9e (11 nm); =Con A (1 mgmLÀ1), 9e
&
*
=Con A (1 mgmLÀ1), 9e (0.6 nm);
=9e (2.0 nm);
~
!
^
=
(2.0 nm);
Con A (1 mgmLÀ1).
This aggregation occurred even at glycopolymer concen-
trations as low as 0.6 nm (Figure 1). This low value indicates
a rather strong interaction between the glycopolymer 9e
and the lectin. The reason for the precipitation is mainly
due to the size of the polymeric backbone and the large
number of ligands (i.e., mannose) at the surface of the poly-
meric material. Around 50 mannose moieties, conjugated to
the surface of 9e, enable multivalent binding of several lec-
tins, eventually resulting in precipitation of glycopolymer/
Con A clusters.
To further quantify the observed strong interaction, the
affinity of 9e towards Con A was studied by an enzyme-
linked lectin assay (ELLA).[15] In this experiment, the ability
of a soluble ligand to inhibit the binding of a lectin to a
polymeric reference ligand noncovalently immobilized on a
titer plate is measured by an IC50 value. This value defines
the concentration of the soluble ligand that is necessary to
inhibit 50% of the adhesion of the lectin to the immobilized
reference ligand. In the present case, a horseradish perox-
idase labeled Con A (HRP-Con A) was used as the lectin
Acknowledgements
SFB 858 is acknowledged for funding. Dr. Kai Siegenthaler is acknowl-
edged for preliminary work and synthesis of a tripeptide. Jens Voskuhl
Chem. Eur. J. 2011, 17, 4090 – 4094
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A. Studer and J.-P. Lindner
and Falko Strotmann are acknowledged for assisting the turbidimetric
measurements and ELLA studies.
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À
Keywords: carboaminoxylation
·
C C coupling
·
lectin
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Received: November 3, 2010
Published online: March 14, 2011
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