A convergent approach to biocompatible polyglycerol "click" dendrons for the synthesis of modular core-shell architectures and their transport behavior

Article abstract of DOI:10.1002/chem.200800892

Dendrimers are an important class of polymeric materials for a broad range of applications in which monodispersity and multivalency are of interest. Here we report on a highly efficient synthetic route towards bifunctional polyglycerol dendrons on a multigram scale. Commercially available triglycerol (1), which is highly biocompatible, was used as starting material. By applying Williamson ether synthesis followed by an ozonolysis/reduction procedure, glycerol-based dendrons up to the fourth generation were prepared. The obtained products have a reactive core, which was further functionalized to the corresponding monoazido derivatives. By applying cop per(I)-catalyzed 1,3-dipolar cycloaddition, so-called "click" coupling, a library of core-shell architectures was prepared. After removal of the 1,2-diol protecting groups, water-soluble coreshell architectures 24-27 of different generations were obtained in high yields. In the structure-transport relationship with Nile red we observe a clear dependence on core size and generation of the polyglycerol dendrons.

Full text of DOI:10.1002/chem.200800892

DOI: 10.1002/chem.200800892
A Convergent Approach to Biocompatible Polyglycerol “Click” Dendrons
for the Synthesis of Modular Core–Shell Architectures and Their Transport
Behavior
Monika Wyszogrodzka and Rainer Haag*[a]
Abstract: Dendrimers are an important
class of polymeric materials for a broad
range of applications in which mono-
dispersity and multivalency are of in-
terest. Here we report on a highly effi-
cient synthetic route towards bifunc-
tional polyglycerol dendrons on a mul-
tigram scale. Commercially available
triglycerol (1), which is highly biocom-
patible, was used as starting material.
By applying Williamson ether synthesis
followed by an ozonolysis/reduction
procedure, glycerol-based dendrons up
to the fourth generation were pre-
pared. The obtained products have a
reactive core, which was further func-
tionalized to the corresponding monoa-
zido derivatives. By applying cop-
per(I)-catalyzed 1,3-dipolar cycloaddi-
tion, so-called “click” coupling, a li-
brary of core–shell architectures was
prepared. After removal of the 1,2-diol
protecting groups, water-soluble core–
shell architectures 24–27 of different
generations were obtained in high
yields. In the structure–transport rela-
tionship with Nile red we observe a
clear dependence on core size and gen-
eration of the polyglycerol dendrons.
Keywords: biocompatibility · click
chemistry · core–shell structures ·
dendrimers · host–guest systems ·
polyglycerol dendrons
Introduction
Vçgtle et al.,[5] Tomalia et al.,[6] and Newkome et al.[7] and
the convergent approach of Hawker and FrØchet—[8] have
been developed for their preparation. The problem of the
structural purity of single molecules in the divergent ap-
proach has been overcome by the convergent growth ap-
proach,[9] wherein the synthesis of dendrimers starts from
the periphery to a polyfunctional core, and thus reduces the
number of reactions performed on a single molecule. Conse-
quently, in the convergent method, each molecule has a pre-
cise molecular weight and structure and can easily be puri-
fied from the incomplete coupling products. Also, the den-
drons can be modified at both ends: the focal point and the
shell.
Dendrimers and dendrons have been known for 30 years
and have entered many research areas, from gene and drug
delivery to diagnostics, as well as nanoengineering.[1] This
relatively new type of macromolecular architecture is suc-
cessfully used in many applications such as surface modifica-
tion,[2] materials science, and catalysis.[3] By taking advant-
age of the multivalency of dendrimers and the possibility to
use almost any type of chemistry for their post-synthetic
chemical modification, they may be used as antiviral, anti-
bacterial, and antitumor agents.[4]
In spite of the attractive properties of dendrimers, only
two types, namely, polyamidoamine (PAMAM, Starburst,
DNT) and poly(propylene imine), PPI (Astramol, DSM),
have been commercialized, because of their tedious, step-
wise, and time-consuming synthesis. So far, two complemen-
tary general methods—the divergent approach initiated by
Dendritic oligoethers[10] have found a wide range of appli-
cations.[11] Much effort has been devoted to the preparation
of dendrimers that are water-soluble and biocompatible. For
example, FrØchet and co-workers synthesized a dendritic an-
alogue of the highly biocompatible poly(ethylene glycol)
(PEG), which is a promising structural skeleton for many
biological applications.[12] Dendritic polyethers based on
glycerol dendrimers prepared by us are also of interest for
biomedical applications due to their high biocompatibility.[13]
Yamamoto et al. reported the convergent preparation of
glycerol-based dendrons by applying Williamson ether for-
mation between a benzyl/dendritic alcohol and epichlorohy-
drin.[14] A carborane unit was linked to these dendrons to
[a] Dipl.-Ing. M. Wyszogrodzka, Prof. Dr. R. Haag
Institut für Chemie und Biochemie
Freie Universität Berlin
Takustrasse 3, 14195 Berlin (Germany)
Fax : (+49)30-838-53357
E-mail: haag@chemie.fu-berlin.de
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200800892.
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FULL PAPER
produce a water-soluble carborane that was used in boron
neutron-capture therapy.
ble bifunctionality using easy synthetic steps. We achieved
our goals by applying a combination of two previously de-
scribed protocols.[23] We used 3-chloro-2-chloromethyl-1-pro-
pene (methallyl dichloride or MDC) as monomer, because
its allylic functionality makes nucleophilic substitution of
both electrophilic sites more attractive. In addition, the
double bond at the focal point can be converted easily and
in high yields to the primary or secondary alcohol by a stan-
dard hydroboration/oxidation protocol[10b,23a] or ozonolysis/
reduction sequence,[23b] respectively. Using Williamson ether
synthesis and an ozonolysis/reduction sequence for subse-
quent activation and growth steps allowed us to prepare bi-
functional polyglycerol dendrons up to the fourth generation
in high yields. Additionally, ozonolysis and hydride reduc-
tion, as opposed to hydroboration with 9-borabicyclo-
We previously reported an efficient divergent method to-
wards polyglycerol dendrimers involving a repetitive se-
quence of allylation and dihydroxylation steps.[15] Recently,
we described a divergent route for the synthesis of bifunc-
tional monoamino glycerol dendrons,[16] in which we also ap-
plied a sequence based on allylation and catalytic dihydrox-
ylation with osmium tetroxide, and obtained [G3] monoami-
no glycerol dendrons in good yields. Park et al. showed that
[G4.0] and [G5.0] polyglycerol dendrimers can solubilize the
poorly water-soluble drug paclitaxel (PTX). The solubility
of PTX increased with increasing generation of dendritic
PG.[17] On the other hand, core–shell-type architectures ob-
tained by simple modification of hyperbranched PG with a
biphenylic unit enhanced the solubilization of highly hydro-
phobic drugs such as Nimodipine.[18]
Since linear and hyperbranched polyglycerol proved to be
highly biocompatible[19] and might be used for many bio-
medical applications, any heavy-metal content would be a
problem. Therefore, an alternative synthetic route to metal-
free dendrimers was our goal. Additionally, optimization of
the reaction and purification steps may improve the synthet-
ic pathway and enable the preparation of large quantities.
Nevertheless, one major drawback remains, that is, the tre-
mendous effort required to obtain these perfect structures.
Furthermore, the ability to execute considerable structural
control by imparting bifunctionality with easy synthetic
steps is required.
The [2+3] Huisgen cycloaddition, rediscovered by Sharp-
less et al.,[20] is growing in impact and has found many appli-
cations in most areas of modern chemistry. The beauty of
this reaction resides in its simplicity, reliability, specificity,
and biocompatibility. Moreover, this copper(I)-catalyzed for-
mation of triazoles tolerates a wide range of functional
groups and many solvents (including water). Recently,
Hawker et al. introduced click coupling into dendrimer syn-
thesis, and demonstrated for the first time the power and ef-
ficiency of this methodology in macromolecular chemistry.[21]
Since then, Huisgen 1,3-dipolar cycloaddition of azides and
alkynes has been utilized in fields of chemistry ranging from
drug discovery to materials science.[22]
AHCTREU[GN 3.3.1]nonane (9-BBN) and oxidation with H2O2, proceeded
smoothly in all cases and gave the desired compounds in
pure form.
As a starting material we chose commercially available
triglycerol (1), the terminal diol units of which were convert-
ed to the corresponding diacetal by catalytic reaction with
acetone dimethylacetal.[24] The acetal protecting group is
stable under strongly basic, reductive, and oxidative condi-
tions.[25] In addition, deprotection of the terminal hydroxy
groups, which can be further modified if desired, can be per-
formed under mild acidic conditions. Even though triglycer-
ol contains a considerable amount of other oligomers, such
as di-and tetraglycerol, we decided that this concept is the
more straightforward approach for scaleup. After acetal pro-
tection [G1.0]-OH (2) can be obtained on a scale of up to
600 g in highly pure form. Alternatively, 2 can also be ob-
tained from acetal-protected glycerol by the procedure
shown in Scheme 1 (bottom).
Here we describe the convergent synthesis of a new
family of core–shell dendrimers with an aliphatic polyether
backbone based on glycerol units. Such well-defined den-
drons have great potential owing to multifunctional chain
ends stemming from an easily functionalizable focal point.
In addition, polyglycerol dendrons with their glycerol build-
ing blocks are biocompatible and can be made water-soluble
or water-dispersible by varying their shell functionality.
Results and Discussion
Synthesis of bifunctional, clickable glycerol dendrons: In
contrast to the divergent approach, convergent protocols
allow us to attain considerable structural control and varia-
Scheme 1. Syntheses of acetal-protected triglycerol.
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R. Haag and M. Wyszogrodzka
Second-generation [G2.0]-ene (6) was synthesized by re-
action of 2.1 equiv of [G1.0]-OH (2) with a suspension of
sodium hydride and MDC in dry THF in the presence of
catalytic amounts of KI, [15]crown-5, and [18]crown-6
(Scheme 2). The presence of [15]crown-5 during deprotona-
tion of the OH group and subsequent addition of [18]crown-
6/KI allows us to generate a more reactive secondary alco-
holate in the core and to improve the coupling yields dra-
matically. Therefore, we did not observe any formation of
monosubstituted MDC. Due to the similar polarity of start-
ing material 2 and [G2.0]-ene (6), purification by column
chromatography on a multigram scale was incomplete.
Therefore, on large scales (up to 100 g), we used HPLC with
2-propanol/n-hexane as eluent to separate all [Gn]-ene
products. The unsaturated compound was then ozonolyzed
and reduced to the secondary alcohol by treatment with
sodium borohydride, and [G2.0]-OH (7) was obtained by
simple extraction in excellent yield and in very pure form.
For all other dendron modifica-
tions column filtration was suf-
ficient for purification.
To synthesize the next gener-
ations, compound 7 was again
treated with MDC in THF, fol-
lowed by the O3/NaBH4 reac-
tion. Both [G3.0]-ene (8) and
[G3.0]-OH (9) were obtained in
very high yields. Up to genera-
tion [G4.0] monosubstitution of
MDC was not observed, but a
significant decrease in yield for
[G4.0]-ene (10) was. This was
attributed to steric hindrance
after the attack of the first den-
dritic alcohol group of com-
pound 9 on MDC and to diffi-
culties in purification. All [Gn]-
ene and [Gn]-OH compounds
were isolated as transparent,
slightly yellow or colorless vis-
cous oils. We also tried to syn-
thesize [G5.0]-ene, but due to
difficulties in purification we
were only able to detect the de-
sired product by ESIMS.
Identification of the focal
functionality by NMR and IR
spectroscopy facilitated charac-
terization of these dendritic
structures, especially for higher
generations. The integration
ratio calculated from 1H NMR
between acetal groups and
focal functionality verified re-
tention of protecting groups
and the number of generations.
The purity of polyether den-
drons was assessed by elemen-
tal analysis and high-resolution
mass spectroscopy.
A single
species was observed in the
mass spectrum corresponding
to the expected isotopic ratio
for [M+H]+, [M+Na]+, and
[M+K]+. In some cases, the
presence of [M+NH4]+ and
Scheme 2. Convergent approach to bifunctional polyglycerol dendrons. a) NaH, [15]crown-5, MDC, [18]crown-
6, KI, THF, reflux, 24 h; b) 1. O3, CH2Cl2/MeOH (1/1), 2. NaBH4.
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Figure 1. ESI-TOF mass spectrum of 25c (m/z 3073.6852).
very strong signals of doubly charged ions were observed
(e.g., ESI-TOF-MS of 25c, Figure 1).
tion sequence was applied to the higher generations of poly-
glycerol dendrons, and the desired monoazides were ob-
tained in excellent yields.
We previously reported a divergent approach to bifunc-
tional glycerol dendrons with azide functionality in the
core.[16] We used the same reaction sequence to functionalize
the focal point of all polyglycerol dendrons with azo groups
(Scheme 3). The free secondary hydroxyl group of [G1.0]-
OH was converted to the corresponding mesylate[26] and
without further purification treated with sodium azide[27] to
give [G1.0]-N3 in 96% yield over two steps. The same reac-
Design and synthesis of modular core–shell architectures
with click dendrons: In designing dendrimers for functionali-
zation by click chemistry, multifunctional azide-or acety-
lene-terminated core molecules are required. Initially, com-
mercially available aromatic oligoacetylene cores 16–18
were chosen for our modular approach with monoazido den-
drons (Scheme 4). In addition, 19 was synthesized according
to the procedure described by Müllen et al.[28] starting from
1,3,5-tris(4-bromophenyl)benzene.[29]
Scheme 3. Synthesis of monoazido glycerol dendrons.
Scheme 4. Oligoacetylene aromatic cores.
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R. Haag and M. Wyszogrodzka
The first click reactions between compounds 16–18 and
[G1.0]-N3 were performed according to the procedure de-
scribed by Sharpless et al.[30] with 5 mol% CuSO4, 10 mol%
ascorbic acid/10 mol% NaOH (to form sodium ascorbate in
situ) in water/THF (1/1) at room temperature. However, the
reaction times were very long and the conversions incom-
plete. Additionally, cleavage of acetal groups was observed,
probably due to incomplete salt formation. Hence, we modi-
fied the coupling procedure, first by excluding the presence
of acid and second by using additional catalyst to shorten
the reaction times. In the course of optimization, we found
that 5–15 mol% of CuSO4, 10–30 mol% of sodium ascor-
bate, and 10–30 mol% of diisopropylethylamine (DIPEA)
were sufficient to generate the desired core–shell structures
in very good yields (Table 1, Scheme 5). As shown in
Table 1, the yields of 20–23 isolated from the coupling of
[G3.0]-N3 to aromatic cores 16–18 were in the range of 30–
44%, mainly due to the steric hindrance of dendrons and
core and difficulties in purification.
Traces of copper salts in the products were easily removed
by washing with a saturated solution of ethylenediaminete-
traacetic acid (EDTA). To obtain high conversions, we tried
to use stoichiometric amounts of the azides (2–3 equiv de-
pending on core functionality), but formation of byproducts
was observed. Therefore, in all cases an excess of 0.1 equiv
of monoazido dendrons per triple bond was used. Purifica-
tion was performed by flash column chromatography or
HPLC.
Finally, the acetal protecting groups were removed in
almost quantitative yield by stirring with an acidic ion-ex-
change resin in methanol to obtain the water-soluble core–
shell architectures (Scheme 6). Because 1,2,3-triazole is a
weak base, the ion-exchange beads were washed with 5%
Et3N in MeOH in order to obtain the desired water-soluble
dendrimers 24–27 in 84–99% yield (Table 1).
Table 1. Yields for click coupling of monoazido glycerol dendrons to the
aromatic cores and after removal of acetal groups.
Entry Aromatic [Gn]-N3 Coupling Yield[a] Deprotection Yield[a]
Structure–transport relationship
core
product
[%]
product
[%]
1
2
3
4
5
6
7
8
9
16
16
16
17
17
17
18
18
18
19
19
19
N
20a
20b
20c
21a
21b
21c
22a
22b
22c
23a
23b
23c
96
97
32
97
78
30
98
91
44
99
87
75
24a
24b
24c
25a
25b
25c
26a
26b
26c
27a
27b
27c
86
99
99
88
95
98
96
84
92
87
87
91
Complex formation with Nile red: We investigated the trans-
port properties of 24–27 by using Nile red, a neutral, poorly
water soluble, and environmentally sensitive fluorescent dye
(Figures 2 and 3). The fluorescence of Nile red strongly de-
pends on the polarity of the environment; it is redshifted in
polar solvents and reaches its maximum blueshift and inten-
sity in nonpolar solvents/environment.[31] The remarkable
sensitivity of Nile red was beneficial in studying the local
polarity of bolaamphihiles,[32] micelles,[33] and interactions
with cyclodextrins.[34] Small changes in the organization of
the surfactants in the solvent system could be monitored
10
11
12
[a] Yields of isolated products.
Scheme 5. Functionalization of the oligoacetylene core by glycerol dendrons: 5–15 mol% CuSO4, 10–30 mol% sodium ascorbate, and 10–30 mol%
DIPEA, THF/H2O (1/1).
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Scheme 6. Removal of the acetal groups: Dowex 50W, MeOH, reflux. Core–shell architectures based on polyglycerol dendrons (coupling with [G2.0] is
shown).
with Nile red,[33c] and the specific properties of this hydro-
phobic dye can also be used to characterize new amphiphilic
molecules and their self-assembly processes.
For the dye solubilization measurements, 2.5 mL of an
aqueous solution of the respective compound at a concen-
tration of 1.0 gLÀ1 and 3 mg of Nile was stirred at room
temperature for 24 h. These saturated solutions were filtered
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R. Haag and M. Wyszogrodzka
Figure 2. UV spectra of the complexes of 27a–c (c=1 mgmLÀ1) with Nile
red.
to remove all solids. Then UV spectroscopy was carried out
at 258C. Calibration curves for Nile red in toluene, acetone,
methanol, and ethanol were recorded by using known con-
centrations of dye in the respective solvent. Assuming that
the extinction coefficients of dye in the solvents are almost
the same as in water, the amount of solubilized Nile red in
the polymer solution can be calculated (see Figure 3). All
saturated aqueous solutions of compounds 24–27 show good
long-term stability (several months).
Figure 3. Structure–transport relationship of core–shell architectures 24–
27 with Nile red (NR). a) mg NR/g polymer. b) mmol NR/mol polymer.
For reasons of clarity the error bars of the UV measurements are not
shown; these deviations are typically in the range of Æ15%.
Characterization of polymer–dye complexes: Figure 3a sum-
marizes the Nile red transport efficiency as a function of
dendrimer generation and the structure of the hydrophobic
core.
Even through Nile red is solubilized by each type of struc-
ture, the highest transport efficiency (w/w) is obtained for
the compounds with the largest hydrophobic core. The high-
est value (6.1 mg Nile red) for this class of substance was
obtained for [G2.0] (Scheme 6, Figures 2 and 3). Neverthe-
less, a clear dependence on the size of the core and the den-
drimer generation can be seen in Figure 3b. As expected,
the transport capacity (mmol dye/mol polymer) of the dye
improved significantly with increasing core size, especially
for [G3.0]. The transport capacity also increases with higher
dendron generation. In contrast to a previous report on pol-
yglycerol dendrons coupled to a biphenyl core by amide
bonds,[16a] here we find a clear and systematic dependence of
complex formation with Nile red on dendrimer generation.
The adsorption spectrum of Nile red is strongly depen-
dent on solvent/environment and shows a large redshift with
increasing solvent/environment polarity.[31a,c] The absorption
spectra (Figure 2) revealed a strong red shift of the absorp-
tion band of Nile red in the [G1.0] dendron complex, with
lmax =585 nm, and a blueshift for [G2.0] and [G3.0] dendron
complexes, with lmax =515 nm. The first shift suggests that a
very polar environment, such as glycerol groups, surrounds
the Nile red molecules. Probably, the hydrophobic cores
coupled with the smallest dendron [G1.0] tend to form ag-
gregates by p–p interactions, and therefore the dye was not
accommodated into the core. In the case of higher genera-
tions, for which the maximum absorption is shifted to lower
wavelengths, Nile red is located more in the hydrophobic
core. The observable band splitting in UV absorbance
(nicely visible for compound 27b) is a typical behavior of
Nile red in nonpolar solvents/environments.[31c] This leads to
the conclusion that an extended aromatic core is required
for efficient encapsulation and transport of hydrophobic
compounds such as Nile red. Especially in comparison to
our previous work[16a] in which polyglycerol dendrons were
attached to a biphenyl core by amide bonds, we significantly
improved the encapsulation of Nile red by a factor of about
200 by increasing both core and dendrimer size, as shown in
Figure 3.
Conclusion
In conclusion, we have demonstrated a new, osmium-free
convergent approach to monoazido polyglycerol dendrons,
as opposed to the traditional divergent pathway. Glycerol
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Polyglycerol “Click” Dendrons
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added followed by slow addition of p-toluenesulfonic acid (PTSA;
15.12 g, 0.125 mol). The reaction was carried out overnight at 30–408C.
After the mixture had been stirred for 0.5 h, a homogeneous solution was
obtained. The resulting yellow-orange solution was neutralized by addi-
tion of triethylamine (0.125 mol) and subsequent stirring for 30 min at
room temperature. Then the solvent was evaporated in vacuo and the re-
maining crude liquid was purified by filtration over silica gel (ethyl ace-
tate/n-hexane 1/2, 2/1, 6/1) or by HPLC (15% 2-propanol in n-hexane) to
give 2 as a pale yellow oil (70–78%; triglycerol contains ca. 20–30%
other oligomers). 1H NMR (500 MHz, [D6]acetone, 258C): d=4.19 (q,
J=11.9, 6.3 Hz, 2H), 4.00 (dd, J=8.2, 6.4 Hz, 2H), 3.84 (m, 1H), 3.75
(td, J=4.9, 1.5 Hz, 1H), 3.69 (dd, J=8.2, 6.3 Hz, 2H), 3.50 (ddd, J=31.8,
10.1, 5.5 Hz; ddd, J=17.4, 11.9, 6.3 Hz, 8H), 2.83 (s, 1H, OH), 1.33 (s,
6H; CH3), 1.28 ppm (s, 6H; CH3); 13C NMR (125 MHz, [D6]acetone,
258C): d=109.4, 75.6, 73.9, 73.8, 73.14, 73.12, 70.17, 67.4, 27.1, 25.7 ppm;
FABMS (m-nitrbenzyl alcohol (mNBA) matrix) found for C15H28O7
(calcd 320.18): m/z (%): 343.2 [M+Na]+, 321.3 [M+H]+; elemental anal-
ysis calcd (%) for C15H28O7 (calcd 320.38): C 56.23, H 8.81; found: C
55.88, H 8.65.
dendrimers are readily accessible on multigram scale up to
the fourth generation, which is an important advantage over
the conventional divergent pathway. Additionally, with this
environment friendly synthetic pathway (less toxic reagents
used in only small excess) we achieved higher structural
purity and could apply simple separation protocols, such as
column filtration.
Furthermore, a library of core–shell architectures 24–27,
based on a variety of aromatic cores and different genera-
tions of highly biocompatible click dendrons, were prepared
by using a click chemistry concept. The unprecedented char-
acteristic properties of the click dendrons, such as easy ac-
cessibility and solubility in water, make them a powerful
tool for the modification of different hydrophobic cores
with highly biocompatible and water-soluble shells. In addi-
tion these new architectures were used as solubilizing agents
for the hydrophobic dye Nile red. The structure–transport
relationship showed a clear dependence on core size and
generation of the polyglycerol dendrons. These new dendrit-
ic polyglycerol architectures with extended aromatic cores
show much higher transport efficiency than the previously
reported biphenyl-based structures.
General procedure for synthesis of [Gn]-ene: [Gn]-OH (1.05 equiv per
Cl), 60% NaH (2.5–5.0 equiv per OH) in mineral oil, cat. [15]crown-5,
and freshly distilled dry THF were placed in a dry two-necked round-bot-
tomed flask under an Ar atmosphere. After the mixture had been stirred
for 2–3 h at 408C, 1.0 equiv of methallyl dichloride and cat. KI and
[18]crown-6 were added to the solution. The mixture was stirred under
reflux for 12–24 h. After the mixture was cooled to room temperature,
the reaction was quenched with distilled water and extracted with di-
chloromethane. The organic layer then was dried over Na2SO4 and the
solvent was removed under vacuum. The residue was purified by HPLC
with 2-propanol/n-hexane as eluent.
Experimental Section
AHCTRE[UNG G1.0]-ene (3): Reaction conditions and workup were as described
above, with solketal 4 (15.0 g, 0.113 mol, 2.1 equiv), NaH (60% in miner-
al oil, 11.18 g, 0.284 mol, 2.5 equiv per OH), MDC (6.25 mL, 54.05 mmol,
1.0 equiv), and cat. KI, [15]crown-5, and [18]crown-6 in THF (150 mL).
Purification of the residue by silica-gel column chromatography (ethyl
General remarks: Reactions requiring dry conditions were carried out in
Schlenk glassware under argon. Dry, analytical-grade solvents were pur-
chased from Acros or Aldrich and used as received. Triglycerol was ob-
tained as a gift from Solvay Chemicals GmbH and used as received.
1H NMR and 13C NMR spectra were recorded on Bruker AB 250 (250
and 67.5 MHz for 1H and 13C, respectively), Bruker ECX 400 (400 and
acetate/n-hexane 1/4) provided
3 (16.93 g, 99%) as a colorless oil.
1H NMR (500 MHz, CDCl3, 258C): d=5.17 (s, 2H), 4.23–4.27 (q, J=
6.0 Hz, 2H), 4.02–4.05 (dd, J=6.4, 8.3 Hz, 2H), 4.0–4.01 (m, 4H), 3.70–
3.73 (dd, J=6.4, 8.2 Hz, 2H), 3.40–3.50 (ddd, J=5.6, 9.9, 34.5 Hz, 4H),
1.39 (s, 6H; CH3), 1.33 ppm (s, 6H; CH3); 13C NMR (125 MHz, CDCl3,
258C): d=142.1, 114.6, 109.4, 74.7, 72.1, 71.2, 66.9, 26.8, 25.5 ppm; IR:
n˜ =2986, 2869, 1455, 1371, 1256, 1214, 1089, 845 cmÀ1; EIMS (408C)
found for C16H28O6 (calcd 316.1886): m/z (%): 316.2 (0.6) [M+], 301.2
(24.5) [M+ÀCH3], 43 (100) [C2H3O+]; elemental analysis calcd (%) for
C16H28O6 (316.39): C 60.74, H 8.92; found: C 60.85, H 8.47.
1
100 MHz for H and 13C, respectively), and Delta JEOL Eclipse 500 (500
and 125 MHz for 1H and 13C, respectively) spectrometers at 258C. AMX
500 and ECX 400 spectrometers were used to record high-resolution
13C NMR spectra. The spectra were calibrated on the solvent peak
(CDCl3: d=7.26 ppm for 1H and d=77.0 ppm for 13C; CD3OD: d=
1
4.84 ppm for H and d=49.05 ppm for 13C; [D6]acetone: d=2.05 ppm for
1H and d=30.83 ppm for 13C). Flash chromatography was performed on
silica gel 60 (230–400 mesh) with head pressure developed by means of
compressed air. IR spectra were recorded on KBr pellets on a Nicolet
5SXC FTIR Interferometer. Elemental analyses were performed on a
Perkin-Elmer EA 240. For ESI-TOF measurements an Agilent 6210 ESI-
TOF (Agilent Technologies, Santa Clara, USA) and for electrospray ioni-
zation Fourier transform ion cyclotron resonance mass spectrometry
(ESI-FTICRMS) measurements an Ionspec QFT-7 (Varian Inc., Lake
Forest, USA) were used. HPLC was carried out on a Knauer HPLC
(pump K-1800) using a Knauer RI-detector K-2401 and a Nucleosil 50-5
(32”240) column. UV measurements were carried out on a S-3100
System UV/Vis spectrometer (SCINCO) at 258C.
AHCTRE[UNG G2.0]-ene (6): Reaction conditions and workup were as described
above, with alcohol 2 (90.0 g, 0.281 mol, 2.1 equiv), NaH (60% in mineral
oil, 28.09 g, 0.702 mol, 2.5 equiv per OH), MDC (15.48 mL, 16.72 g,
133.8 mmol, 1.0 equiv), cat. KI, [15]crown-5, and [18]crown-6 in THF
(650 mL). Purification of the residue by by HPLC (25% 2-propanol in n-
hexane) gave 6 (87.1 g, 94%) as a colorless oil. 1H NMR (500 MHz,
CDCl3, 258C): d=5.15 (dd, J=4.7, 13.2 Hz, 2H), 4.23–4.27 (2”q, J=6.1,
5.7 Hz, 4H), 4.09 (d, J=10.2 Hz, 3H), 4.02–4.05 (dd, J=6.6, 8.1 Hz, 4H),
3.96 (d, J=11.6 Hz, 1H), 3.72–3.70 (m, J=8.2 Hz, 4H), 3.65–3.51 (brm,
14H), 3.45 (dt, J=5.7, 9.6 Hz, 4H), 1.37 (s, 12H; CH3), 1.33 ppm (s,
12H; CH3); 13C NMR (125 MHz, CDCl3, 258C): d=143.0, 114.1, 109.3,
78.62, 78.60, 74.71, 74.69, 74.55, 74.54, 72.43, 72.41, 71.5, 71.3, 70.7, 70.1,
66.9, 66.7, 26.7, 25.3 ppm; IR: n˜ =2986, 2875, 1456, 1371, 1256, 1214,
1082, 975, 918, 885 cmÀ1; EIMS (1208C) found for C34H60O14 (calcd
692.3983): m/z (%): 692.3 (1.5) [M+], 677.2 (34.9) [M+ÀCH3], 114.9
(100) [C6H11O2+], 101.0 (90.1) [C5H9O2+], 55 (33.3) [C3H3O+], 42.9
(37.8) [C2H3O+].
Typical encapsulation procedure and determination of transport capacity:
Compounds 24–27 were dissolved in Milli-Q water (2.5 mL) at a concen-
tration of 1.0 gLÀ1, and Nile red (3 mg) as a fine powder was added. The
obtained suspension was stirred vigorously for 24 h with a magnetic stir-
rer at 1000 rpm. Next the insoluble solid residue of the dye was removed
by filtration through a 0.2 mm cellulose acetate filter (Whatman), and the
obtained clear solution was analyzed by UV/Vis spectroscopy. Obtained
adsorptions were compared with a calibration curve of the Nile red to de-
termine the concentration of the guest molecule in the solution. The UV/
Vis spectra were recorded from 220 to 1000 nm with water as reference.
AHCTRE[UNG G3.0]-ene (8): Reaction conditions and workup were as described
above, with alcohol 7 (50.0 g, 71.75 mmol, 2.1 equiv), NaH (60% in min-
eral oil, 14.35 g, 0.36 mol, 5 equiv per OH), MDC (3.95 mL, 4.27 g,
34.17 mmol, 1.0 equiv), cat. KI, [15]crown-5, and [18]crown-6 in THF
(400 mL). Purification of the residue by HPLC (50% 2-propanol in n-
hexane) gave 8 (45.4 g, 92%) as a colorless oil. 1H NMR (250 MHz,
Acetal protection of triglycerol (1) to give (2): Triglycerol (1; 300 g,
1.25 mol) was gently heated with a heat gun (max. 1208C) until it took
on a liquid consistency. 2,2-dimethoxypropane (0.608 L, 4.995 mol) was
Chem. Eur. J. 2008, 14, 9202 – 9214
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
9209

R. Haag and M. Wyszogrodzka
CDCl3, 258C): d=5.15 (s, 2H), 4.22 (q, J=5.8 Hz, 8H), 4.03 (dd, J=6.9,
13.6 Hz, 8H), 4.01 (s, 4H), 3.70 (dd, J=6.6, 7.9 Hz, 8H), 3.77–3.41 (brm,
46H; CH2CH backbone), 1.39 (s, 24H; CH3), 1.33 ppm (s, 24H; CH3);
13C NMR (125 MHz, CDCl3, 258C): d=143.1, 113.6, 109.3, 78.4, 74.71,
74.6, 74.55, 74.54, 72.4, 72.41, 71.5, 71.3, 70.7, 70.1, 66.9, 66.7, 26.7,
25.4 ppm; IR: n˜ =2985, 2874, 1456, 1371, 1256, 1214, 1083, 845 cmÀ1; ESI-
TOF-MS found for C70H124O30 (calcd 1444.8177): m/z (%): 1445.8227
[M+H]+, 1467.8045 [M+Na]+; elemental analysis calcd (%) for
C70H124O30 (1445.72): C 58.15, H 8.65; found: C 58.08, H 8.24.
3.68 (m, 20H), 3.64–3.41 (brm, 102H; CH2CH backbone), 2.97 (brs, 1H;
OH), 1.36 (s, 48H; CH3), 1.30 ppm (s, 48H; CH3); 13C NMR (125 MHz,
CDCl3, 258C): d=109.2, 78.51, 78.29, 78.22, 74.62, 74.49, 72.38, 71.50,
71.35, 71.24, 71.05, 70.23, 69.85, 69.57, 66.79, 66.68, 26.72, 25.35 ppm; IR:
n˜ =3501, 2985, 2875, 1456, 1371, 1256, 1214, 1106, 975, 844, 515 cmÀ1
;
ESI-TOF-MS found for C141H252O63 (calcd 2953.6515): m/z (%):
2954.6738 [M+H]+, 2976.6684 [M+Na]+; 2992.6075 [M+K] +; elemental
analysis calcd (%) for C141H252O63 (2955.4718): C 57.30, H 8.59; found: C
56.98, H 8.62.
ACHTREUNG[G4.0]-ene (10): Reaction conditions and workup were as described
General procedure for the synthesis of azide dendrons [Gn]-N3: Metha-
nesulfonyl chloride (MsCl, 1.1–3.0 equiv) was added to a solution of
[Gn]-OH (1.0 equiv) and triethylamine (1.1–3.0 equiv) in toluene cooled
to 08C in an ice bath. Progress of the reaction was monitored by TLC.
After completion, the precipitate was removed by filtration and the mix-
ture concentrated under vacuum to give the final product (100%). The
crude product was used for next reaction step. NaN3 (2.5–5.0 equiv) was
added to a solution of [Gn]-OMs (1.0 equiv) in dry DMF. After the mix-
ture had been stirred at 1208C under argon for 3 h, excess NaN3 was fil-
tered off and DMF was removed under high vacuum by cryodistillation.
The crude product was purified by filtration over a thin layer of silica gel
(ethyl acetate/n-hexane). [Gn]-N3 was obtained as a light yellow, viscous
oil.
above, with alcohol 9 (25.0 g, 17.25 mmol, 2.1 equiv), NaH (60% in min-
eral oil, 3.45 g, 86.25 mmol, 5 equiv per OH), MDC (0.95 mL, 1.03 g,
8.21 mmol, 1.0 equiv), cat. KI, [15]crown-5, and [18]crown-6 in THF
(220 mL). Purification of the residue by by HPLC (50% 2-propanol in n-
hexane) gave 10 (15.9 g, 66%) as a colorless oil. 1H NMR (500 MHz,
CDCl3, 258C): d=5.15 (s, 2H), 4.21 (m, 16H), 4.02 (m, 20H), 3.70 (m,
16H), 3.63–3.42 (brm, 102H; CH2CH backbone), 1.37 (s, 48H; CH3),
1.33 ppm (s, 48H; CH3); 13C NMR (67.5 MHz, CDCl3, 258C): d=143.2,
112.73, 109.23, 78.78, 78.60, 78.35, 78.28, 74.70, 74.54, 72.44, 71.97, 71.68,
71.55, 71.42, 71.30, 71.14, 70.58, 70.15, 69.93 66.88, 66.75, 26.76,
25.38 ppm; IR: n˜ =2985, 2874, 1456, 1371, 1256, 1214, 1083, 844 cmÀ1
;
ESI-TOF-MS found for
C142H252O62 (calcd 2949.6566): m/z (%):
2950.6563 [M+H]+, 2972.6260 [M+Na]+; elemental analysis calcd (%)
AHCTREU[NG G1.0]-N3 (12): Reaction conditions and workup were as described
for C142H252O62 (2951.48): C 57.79, H 8.61; found: C 57.52, H 8.92.
above, with 2 (20.0 g, 62.43 mmol, 1.0 equiv), Et3N (9.21 mL, 65.55 mmol,
1.1 equiv), MsCl (5.06 mL, 65.55 mmol, 1.1 equiv) in toluene (160 mL).
The crude product [G1.0]-OMs (62.43 mmol, 1.0 equiv) was treated with
NaN3 (10.2 g, 0.157 mol, 2.5 equiv) in dry DMF (150 mL). Filtration
through a thin layer of silica gel (ethyl acetate/n-hexane 2/1) gave 12
General procedure for the synthesis of [Gn]-OH: [Gn]-ene (1.0 equiv)
was dissolved in dry MeOH/CH2Cl2 (1/1, c=0.13 molLÀ1) and cooled to
À788C. Ozone was bubbled through the solution until it turned blue.
After the removal of excess ozone with a vigorous stream of oxygen,
sodium borohydride (10.0 equiv) was added. While stirring for 12–15 h
the mixture was allowed to slowly warm to room temperature. The reac-
tion mixture was quenched by addition of saturated NH4Cl solution fol-
lowed by stirring for 1–2 h. The phases were separated and the aqueous
layer was extracted with dichloromethane. The combined organic phases
were washed with water, dried over anhydrous Na2SO4, and filtered.
Evaporation of the solvent yielded the target compound in pure form.
(20.7 g, 96%) as
a
light yellow, viscous oil. 1H NMR (500 MHz,
[D6]acetone, 258C): d=4.21 (q, J=11.7, 6.2, 5.6 Hz, 2H), 4.03 (ddd, J=
8.2, 6.4, 1.0 Hz, 2H), 3.76 (m, 1H), 3.72 (dd, J=8.2, 6.3 Hz, 2H), 3.67
(tdd, J=9.6, 7.8, 4.5 Hz, 2H), 3.61 (ddd, J=5.5, 5.0, 2.2 Hz, 2H), 3.54
(ddd, J=17.9, 10.3, 5.1 Hz, 4H), 1.34 (s, 6H; CH3), 1.28 ppm (s, 6H;
CH3); 13C NMR (125 MHz, [D6]acetone, 258C): d=109.6, 75.51, 75.50,
73.0, 72.9, 71.7, 71.6, 67.2, 61.5, 27.1, 25.7 ppm; IR: n˜ =2987, 2935, 2875,
T
2100, 1456, 1380, 1371, 1258, 1214, 1081, 1055, 975, 844, 515 cmÀ1
;
3
FABMS (mNBA) found for C15H27N3O6 (calcd 345.39): m/z (%): 346.3
[M+H]+, 368.2 [M+Na]+; elemental analysis calcd (%) for C15H27N3O6
(345.39): C 52.16, H 7.88, N 12.17; found: C 52.03, H 7.46, N 11.84.
0.316 mol, 10.0 equiv) in CH2Cl2/MeOH (30 mL). Extraction with CH2Cl2
yielded 2 (10.0 g, 99.0%) as a colorless oil.
ACHTREUNG
AHCTREU[NG G2.0]-N3 (13): Reaction conditions and workup were as described
6
above, with 7 (25.0 g, 35.88 mmol, 1.0 equiv), Et3N (5.45 mL, 39.46 mmol,
1.1 equiv), and MsCl (3.04 mL, 39.46 mmol, 1.1 equiv) in toluene
(150 mL). The crude product [G2.0]-OMs (35.88 mmol, 1.0 equiv) was
treated with NaN3 (11.68 g, 0.179 mol, 5.0 equiv) in dry DMF (150 mL).
Filtration through a thin layer of silica gel (ethyl acetate/n-hexane 6/1)
gave 13 (25.6 g, 99%) as a light yellow, viscous oil. 1H NMR (500 MHz,
CDCl3, 258C): d=4.22 (qtd, J=3.0, 5.9, 8.7 Hz, 4H), 4.02 (dd, J=6.6,
8.1 Hz, 4H), 3.71 (dd, J=7.3 Hz, 5H), 3.67–3.51 (m, 18H), 3.47 (dt, J=
5.3, 10.3 Hz, 4H), 1.36 (s, 12H; CH3), 1.39 ppm (s, 12H; CH3); 13C NMR
(125 MHz, CDCl3, 258C): d=109.3, 78.4, 74.6, 74.5, 72.4, 71.6, 71.4, 71.1,
66.7, 66.6, 60.5, 26.7, 25.3 ppm; IR (KBr): n˜ =2986, 2934, 2874, 2100,
1456, 1380, 1371, 1258, 1214, 1082, 1055, 975, 844, 515 cmÀ1; ESI-TOF-
MS found for C33H59O14N3 (calcd 721.3997): m/z (%): 722.4001 [M+H]+,
744.3880 [M+Na]+, 760.3622 [M+K]+.
0.933 mol, 10.0 equiv) in CH2Cl2/MeOH (720 mL). Extraction with
CH2Cl2 yielded 7 (64.9 g, 99.9%) as a colorless oil. 1H NMR (500 MHz,
CDCl3, 258C): d=4.22 (2”q, J=6.2 Hz, 4H), 4.01 (dd, J=6.9, 7.7 Hz,
4H), 3.86 (tt, J=5.5, 10.9 Hz, 1H), 3.69 (m, 4H), 3.65 (m, 4H), 3.57–3.44
(brm, 18H), 3.18 (brs, 1H; OH), 1.39 (s, 12H; CH3), 1.32 ppm (s, 12H;
CH3); 13C NMR (125 MHz, CDCl3, 258C): d=109.3 (4C), 78.6, 74.5, 72.4,
71.9 71.7, 71.6, 69.7, 66.7, 26.7, 25.3 ppm; IR: n˜ =3490, 2986, 2876, 1456,
1371, 1257, 1214, 1081, 975, 844, 515 cmÀ1; FABMS found for C33H60O15
(calcd 696.3932): m/z (%): 719.4 [M+Na]+; elemental analysis calcd (%)
for C33H60O15 (696.8205): C 56.88, H 8.68; found: C 56.73, H 8.81.
ACHTREUNG
8
0.242 mol, 10.0 equiv) in CH2Cl2/MeOH (200 mL). Extraction with
CH2Cl2 yielded 9 (34.8 g, 99.1%) as a colorless oil. 1H NMR (500 MHz,
CDCl3, 258C): d=4.2 (m, 8H), 4.01 (m, 8H), 3.82 (m, 1H), 3.72–3.41
(brm, 59H; CH2CH backbone, OH), 1.37 (s, 24H; CH3), 1.32 ppm (s,
24H; CH3); 13C NMR (67.5 MHz, CDCl3, 258C): d=109.3, 78.4, 74.7,
74.6, 72.4, 71.5, 71.2, 70.4, 66.7, 26.7, 25.4 ppm; IR: n˜ =3460, 2986, 2878,
1727, 1456, 1372, 1257, 1215, 1082, 975, 844 cmÀ1; ESI-TOF-MS found for
C69H124O31 (calcd 1448.8127): m/z (%): 1449.8207 [M+H]+, 1466.8479
[M+NH4]+, 1471.8041 [M+Na]+; elemental analysis calcd (%) for
C69H124O31 (1449.7043): C 57.17, H 8.62; found: C 56.87, H 8.60.
AHCTREU[NG G3.0]-N3 (14): Reaction conditions and workup were as described
above, with 9 (7.0 g, 4.83 mmol, 1.0 equiv), Et3N (1.34 mL, 9.66 mmol,
2.0 equiv), and MsCl (0.75 mL, 9.66 mmol, 2.0 equiv) in toluene (60 mL).
The crude product [G3.0]-OMs (4.83 mmol, 1.0 equiv) was treated with
NaN3 (1.57 g, 24.14 mmol, 5.0 equiv) in dry DMF (60 mL). Filtration
through a thin layer of silica gel (ethyl acetate/n-hexane 10/1) gave 14
(6.5 g, 91%) as a light yellow, viscous oil. 1H NMR (500 MHz, CDCl3,
258C): d=4.22 (m, 8H), 4.02 (dd, J=6.5, 8.2 Hz, 8H), 3.70 (dd, J=6.3,
8.3 Hz, 8H), 3.77–3.42 (brm, 51H; CHCH2 backbone), 1.39 (s, 24H;
CH3), 1.33 ppm (s, 24H; CH3); 13C NMR (125 MHz, CDCl3, 258C): d=
109.3, 79.0, 78.8, 78.4, 78.3, 74.7, 74.5, 72.4, 71.5, 71.4, 71.2, 70.3, 66.7,
66.6, 60.4, 26.8, 25.4 ppm; IR: n˜ =2986, 2934, 2874, 2100, 1456, 1380,
1371, 1258, 1214, 1082, 1055, 975, 844, 515 cmÀ1; ESI-TOF-MS found for
ACHTREUNG[G4.0]-OH (11): Reaction conditions and workup were as described
above, with 10 (10.0 g, 3.39 mmol, 1.0 equiv) and NaBH4 (1.28 g,
33.88 mmol, 10.0 equiv) in CH2Cl2/MeOH (30 mL). Extraction with
CH2Cl2 yielded 11 (10.0 g, 99.9%) as a colorless oil. 1H NMR (500 MHz,
CDCl3, 258C): d=4.20 (p, J=5.8 Hz, 16H), 4.00 (m, 16H), 3.80 (m, 1H),
C69H123O30N3 (calcd 1473.8191): m/z (%): 759.9144 [M+2Na]2+
,
9210
www.chemeurj.org
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2008, 14, 9202 – 9214

Polyglycerol “Click” Dendrons
FULL PAPER
1496.8243 [M+Na]+; elemental analysis calcd (%) for C69H123N3O30
(1474.72): C 56.20, H 8.41, N 2.85; found: C 56.10, H 8.61, N 3.03.
1.356 mmol, 2.2 equiv), DIPEA (10.2 mL, 0.062 mmol, 0.1 equiv), sodium
ascorbate (24.4 mg, 0.123 mmol, 0.2 equiv), and copper(II) sulfate penta-
hydrate (15.4 mg, 0.062 mmol, 0.1 equiv) in THF/H2O (10 mL). Purifica-
tion by HPLC (2% MeOH in CH2Cl2) gave 20c (0.6 g, 32%). 1H NMR
(500 MHz, CDCl3, 258C): d=8.40–8.34 (m, 1H), 8.13 (m, 2H), 7.74, 7.73
(2s, 2H), 7.43 (t, 1H, J=7.6 Hz), 4.88 (m, 2H), 4.17 (m, 16H), 4.04 (m,
8H), 3.98 (m, 16H), 3.62 (m, 20H), 3.57–3.36 (brm, 86H), 1.34 (s, 24H;
CH3), 1.28 ppm (s, 24H; CH3); 13C NMR (67.5 MHz, CDCl3, 258C): d=
146.47, 131.57, 130.78, 129.10 (C-2), 125.05, 122.53, 122.51, 120.74, 109.22,
79.06, 78.80, 78.51, 78.31, 74.67, 74.53, 72.39, 71.48, 71.40, 71.24, 71.18,
70.29, 69.28, 66.80, 66.75, 66.62, 61.26, 26.71, 25.34 ppm; ESI-TOF-MS
ACHTREUNG[G4.0]-N3 (15): Reaction conditions and workup were as described
above, with 11 (6.0 g, 2.03 mmol, 1.0 equiv), Et3N (0.86 mL, 6.09 mmol,
3.0 equiv), and MsCl (0.47 mL, 6.09 mmol, 3.0 equiv) in toluene (40 mL).
The crude product [G4.0]-OMs (2.03 mmol, 1.0 equiv) was treated with
NaN3 (0.66 g, 10.15 mmol, 5.0 equiv) in dry DMF (50 mL). Filtration
through a thin layer of silica gel (2-propanol/n-hexane 1/1) gave 15
(6.02 g, 99.5%) as a light yellow, viscous oil. 1H NMR (500 MHz, CDCl3,
258C): d=4.21 (m, 16H), 4.01 (m, 16H), 3.80 (m, 1H), 3.69 (m, 20H),
3.64–3.42 (brm, 102H; CH2CH backbone), 1.38 (s, 48H; CH3), 1.32 ppm
(s, 48H; CH3); 13C NMR (125 MHz, CDCl3, 258C): d=109.25, 79.08,
78.78, 78.58, 78.29, 74.70, 74.56, 72.46, 71.31, 71.14, 69.91, 66.92, 66.77,
61.68, 26.78, 25.41 ppm; IR: n˜ =2985, 2875; 2101, 1456, 1371, 1257, 1214,
1108, 975, 844, 515 cmÀ1; ESI-TOF-MS found for C141H251N3O62 (calcd
found for
C148H252N6O60 (calcd 3073.6852): m/z (%): 1537.8480
[M+2H]2+, 1559.8312 [M+2Na]2+; elemental analysis calcd (%) for
C148H252N6O60 (3075.5887): C 57.80, H 8.26, N 2.73; found: C 57.54, H
7.88, N 2.99.
2978.6580): 1015.8753 [M+3Na]3+
[M+2Na]2+, 3001.6304 [M+Na]+.
, , 1512.3181
1490.3352 [M+2H]2+
Ph-1,4-click-[G1.0] (21a): Reaction conditions and workup were as de-
scribed above, with 17 (0. 498 g, 3.948 mmol, 1.0 equiv), 12 (3.0 g,
8.686 mmol, 2.2 equiv), DIPEA (65.2 mL, 0.395 mmol, 0.1 equiv), sodium
ascorbate (156.4 mg, 0.79 mmol, 0.2 equiv), and copper(II) sulfate penta-
hydrate (98.6 mg, 0.395 mmol, 0.1 equiv) in THF/H2O (16 mL). Purifica-
tion by column chromatography (ethyl acetate/n-hexane (6:1) and 5%
MeOH in CH2Cl2) gave 21a (3.071 g, 97%). 1H NMR (500 MHz, CDCl3,
258C): d=8.11–8.0 (m, 2H), 7.87 (m, 4H), 4.94 (q, 1H, J=5.4 Hz), 4.62
(m, 1H), 4.47 (m, 1H), 4.20 (m, 4H), 3.97 (m, 10H), 3.74–3.43 (brm,
13H), 1.39–1.29 ppm (m, 24H; CH3); 13C NMR (125 MHz, CDCl3, 258C):
d=147.0, 130.32, 125.90, 121.48, 121.34, 120.17, 109.48, 109.43, 77.74,
74.68, 74.60, 74.50, 74.41, 72.47, 72.13, 71.26, 71.21, 70.35, 70.18, 70.11,
70.06, 70.0, 66.34, 66.16, 60.45, 51.15, 26.64, 25.22 ppm; IR: n˜ =3567,
3137, 2985, 2878, 1772, 1482, 1456, 1371, 1214, 1054, 973, 841, 735, 698,
516 cmÀ1; QFTESIMS found for C40H60N6O12 (calcd 816.4269): m/z (%):
817.4342 [M+H]+, 839.4152 [M+Na]+, 855.3858 [M+K]+; elemental
analysis calcd (%) for C40H60N6O12 (816.94): C 58.81, H 7.40, N 10.29;
found: C 58.71, H 7.29, N 10.10.
General procedure for the coupling of azide dendrons to the aromatic
core: DIPEA (10–30 mol% per triple bond) was added to 1.0 equiv of
oligoacetylene core (16–19) and 1.1 equiv of [Gn]-N3 per triple bond dis-
solved in THF. After the mixture had been stirred for 5 min, 10–
30 mol% per triple bond of sodium ascorbate was added, followed by 5–
15 mol% of CuSO4·5H2O per triple bond. (A stock solution of sodium
ascorbate and CuSO4·5H2O in water was prepared in concentration
100 mg/mL) The THF/H2O ratio must be 1/1 (v/v). The heterogeneous
mixture was stirred vigorously until TLC analysis indicated complete
consumption of the starting material. The reaction mixture was diluted
with water and extracted with dichloromethane. The combined organic
layers were washed with a small amount of saturated solution of EDTA,
dried with Na2SO4, and concentrated in vacuo. Purification by column
chromatography or HPLC gave the desired product.
Ph-1,3-click-[G1.0] (20a): Reaction conditions and workup were as de-
scribed above, with 16 (0. 498 g, 3.948 mmol, 1.0 equiv), 12 (3.0 g,
8.686 mmol, 2.2 equiv), DIPEA (65.2 mL, 0.395 mmol, 0.1 equiv), sodium
ascorbate (156.4 mg, 0.79 mmol, 0.2 equiv), and copper(II) sulfate penta-
hydrate (98.6 mg, 0.395 mmol, 0.1 equiv) in THF/H2O (16 mL). Purifica-
tion by column chromatography (ethyl acetate/n-hexane (6/1) and 5%
MeOH in CH2Cl2) gave 20a (3.021 g, 95.6%). 1H NMR (500 MHz,
CDCl3, 258C): d=8.26 (s, 1H), 8.10–8.0 (m, 2H), 7.77 (m, 2H,), 7.42 (t,
1H, J=7.7 Hz), 4.90 (m, 2H), 4.93 (q, 1H, J=5.6 Hz), 4.63 (m, 1H), 4.45
(m, 1H), 4.18 (m, 4H), 3.96 (m, 10H), 3.72–3.41 (m, 13H), 1.39–
1.29 ppm (m, 24H; CH3); 13C NMR (125 MHz, CDCl3, 258C): d=147.15,
146.93, 131.17, 129.15, 125.09, 122.66, 121.60, 121.46, 120.25, 120.17,
109.39, 109.36, 98.10, 77.68, 74.55, 74.42, 74.36, 72.62, 72.40, 72.31, 72.10,
71.56, 70.34, 70.07, 70.0, 66.31, 66.14, 60.54, 60.46, 60.39, 51.25, 51.10,
26.57, 25.17 ppm; IR: n˜ =3567, 3135, 2985, 2877,1618, 1456, 1371, 1215,
1054, 974, 841, 798, 698, 516 cmÀ1; ESI-TOF-MS found for C40H60N6O12
(calcd 816.4269): m/z (%): 817.4346 [M+H]+, 839.4167 [M+Na]+,
855.3911 [M+K]+; elemental analysis calcd (%) for C40H60N6O12
(816.94): C 58.81, H 7.40, N 10.29; found: C 58.36, H 7.19, N 10.21.
Ph-1,4-click-[G2.0] (21b): Reaction conditions and workup were as de-
scribed above, with 16 (0.25 g, 1.982 mmol, 1.0 equiv), 13 (3.15 g,
4.36 mmol, 2.2 equiv), DIPEA (32.7 mL, 0.198 mmol, 0.1 equiv), sodium
ascorbate (78.5 mg, 0.396 mmol, 0.2 equiv), and copper(II) sulfate penta-
hydrate (49.5 mg, 0.198 mmol, 0.1 equiv) in THF/H2O (16 mL). Purifica-
tion by column chromatography (ethyl acetate/n-hexane (6/1) and 5%
MeOH in CH2Cl2) gave 21b (2.42 g, 78%). 1H NMR (500 MHz, CDCl3,
258C): d=8.05, 8,01, 7.97, 7.96 (m, 2H), 7.86 (s, 4H), 4.90 (m, 2H), 4.17
(m, 8H), 4.06 (m, 5H), 3.95 (m, 11H), 3.62 (m, 12H), 3.57–3.36 (brm,
32H), 1.34 (s, 24H; CH3), 1.26 ppm (s, 24H; CH3); 13C NMR (125 MHz,
CDCl3, 258C): d=146.63, 130.35, 125.85, 120.10, 109.26, 78.63, 78.31,
74.67, 74.62, 74.50, 72.38, 71.60, 71.47, 71.29, 71.16, 70.18, 69.27, 66.56,
66.41, 61.20, 60.92, 26.64, 25.24 ppm; ESI-TOF-MS found for
C76H124N6O28 (calcd 1568.8464): m/z (%): 1569.8650 [M+H]+, 1591.8483
[M+Na]+.
Ph-1,4-click-[G3.0] (21c): Reaction conditions and workup were as de-
scribed above, with 16 (77.8 mg, 0.616 mmol, 1.0 equiv), 14 (2.0 g,
1.356 mmol, 2.2 equiv), DIPEA (10.2 mL, 0.062 mmol, 0.1 equiv), sodium
ascorbate (24.4 mg, 0.123 mmol, 0.2 equiv), and copper(II) sulfate penta-
hydrate (15.4 mg, 0.062 mmol, 0.1 equiv) in THF/H2O (10 mL). Purifica-
tion by HPLC (2% MeOH in CH2Cl2) gave 21c (0.56 g, 30%). 1H NMR
(500 MHz, CDCl3, 258C): d=8.09 (m, 2H), 7.88 (s, 4H), 4.83 (m, 2H),
4.18 (m, 16H), 4.04 (m, 7H), 3.98 (m, 17H), 3.66 (m, 20H), 3.57–3.38
(brm, 86H), 1.36 (s, 48H; CH3), 1.30 ppm (s, 48H; CH3); 13C NMR
(67.5 MHz, CDCl3, 258C): d=146.36, 130.50, 125.85, 120.10, 109.22,
79.05, 78.81, 78.50, 78.31, 74.66, 74.52, 72.39, 71.49, 71.38, 71.19, 70.13,
69.27, 66.78, 66.60, 61.24, 26.69, 25.32 ppm; ESI-TOF-MS found for
Ph-1,3-click-[G2.0] (20b): Reaction conditions and workup were as de-
scribed above, with 16 (0.25 g, 1.982 mmol, 1.0 equiv), 13 (3.15 g,
4.36 mmol, 2.2 equiv), DIPEA (32.7 mL, 0.198 mmol, 0.1 equiv), sodium
ascorbate (78.5 mg, 0.396 mmol, 0.2 equiv), and copper(II) sulfate penta-
hydrate (49.5 mg, 0.198 mmol, 0.1 equiv) in THF/H2O (16 mL). Purifica-
tion by column chromatography (ethyl acetate/n-hexane (6/1) and 5%
MeOH in CH2Cl2) gave 20b (3.01 g, 97%). 1H NMR (500 MHz, CDCl3,
258C): d=8.31 (s, 1H), 8.11, 8,07, 8,02 (m, 2H), 7.76 (brs, 2H,), 7.43 (t,
1H, J=7.7 Hz), 4.90 (m, 2H), 4.17 (m, 8H), 4.05 (m, 5H), 3.95 (m,
11H), 3.62 (m, 12H), 3.57–3.36 (brm, 32H), 1.34 (s, 24H; CH3),
1.28 ppm (s, 24H; CH3); 13C NMR (125 MHz, CDCl3, 258C): d=146.70,
146.60, 131.39, 131.31, 129.19, 125.02, 122.51, 120.48, 120.29, 109.25,
109.18, 78.65, 78.33, 74.69, 74.64, 74.51, 72.40, 71.64, 71.46, 71.30, 70.18,
69.27, 66.58, 66.43, 61.18, 60.93, 26.65, 25.26 ppm; ESI-TOF-MS found for
C76H124N6O28 (calcd 1568.8464): m/z (%): 1569.8499 [M+H]+, 1591.8315
[M+Na]+, 1607.8075 [M+K]+.
C148H252N6O60 (calcd 3073.6852): m/z (%): 1537.8454 [M+2H]2+
,
1548.8356
[M+H+Na]2+
,
1559.8268
[M+2Na]2+
,
1567.8268
[M+Na+K]2+
;
elemental analysis calcd (%) for C148H252N6O60
(3075.5887): C 57.80, H 8.26, N 2.73; found: C 57.76, H 8.31, N 3.08.
Ph-1,3,5-click-[G1.0] (22a): Reaction conditions and workup were as de-
scribed above, with 18 (0.2 g, 1.332 mmol, 1.0 equiv), 12 (1.518 g,
4.395 mmol, 3.3 equiv), DIPEA (33.0 mL, 0.1998 mmol, 0.15 equiv),
sodium ascorbate (79.2 mg, 0.3996 mmol, 0.3 equiv), and copper(II) sul-
Ph-1,3-click-[G3.0] (20c): Reaction conditions and workup were as de-
scribed above, with 16 (77.8 mg, 0.616 mmol, 1.0 equiv), 14 (2.0 g,
Chem. Eur. J. 2008, 14, 9202 – 9214
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
9211

R. Haag and M. Wyszogrodzka
fate pentahydrate (50.0 mg, 0.1998 mmol, 0.15 equiv) in THF/H2O
(14 mL). Purification by column chromatography (ethyl acetate/n-hexane
(6/1) and 5% MeOH in CH2Cl2) gave 22a (1.55 g, 98.3%). 1H NMR
(500 MHz, CDCl3, 258C): d=8.31 (s, 3H), 8.15 (m, 3H), 4.98 (q, 3H, J=
5.6 Hz), 4.22 (m, 6H), 3.99 (m, 18H), 3.64 (m, 6H), 3.55–3.47 (m, 12H),
1.37 (s, 18H; CH3), 1.31 ppm (s, 18H; CH3); C13 NMR (125 MHz, CDCl3,
258C): d=146.9, 131.9, 122.4, 120.7, 109.7, 74.7, 72.7, 72.4, 70.4, 70.3,
66.4, 60.9, 26.8, 25.4 ppm; ESI-TOF-MS found for C57H87N9O18 (calcd
1185.6169): m/z (%): 1186.6277 [M+H]+, 1208.6104 [M+Na]+, 1224.5849
[M+K]+.
66.45, 61.24, 60.98, 26.66, 25.26 ppm; QFT-ESI MS found for
C129H195N9O42 (calcd 2542.3400): m/z (%): 1272.1793 [M+2H]2+
.
Ph-Ph-1,3,5-click-[G3.0] (23c): Reaction conditions and workup were as
described above, with 19 (0.19 g, 0.502 mmol, 1.0 equiv), 14 (2.443 g,
1.657 mmol, 3.3 equiv), DIPEA (74.5 mL, 0.226 mmol, 0.9 equiv), sodium
ascorbate (89.5 mg, 0.452 mmol, 0.9 equiv), and copper(II) sulfate penta-
hydrate (56.4 mg, 0.226 mmol, 0.45 equiv) in THF/H2O (8 mL). Purifica-
tion by column chromatography (35% 2-propanol in n-hexane and 10%
MeOH in CH2Cl2) gave 23c (1.73 g, 72%). 1H NMR (500 MHz, CDCl3,
258C): d=8.11 (brs, 3H), 7.95 (d, 6H, J=7.7 Hz), 7.83 (s, 3H), 7.76 (d,
6H, J=7.9 Hz), 4.89 (m, 3H), 4.17 (m, 24H), 4.07 (m, 9H), 3.98 (m,
24H), 3.64–3.41 (brm, 165H), 1.37 (s, 72H), 1.31 ppm (s, 72H); 13C NMR
(125 MHz, CDCl3, 258C): d=146.33, 141.74, 140.34, 130.28, 127.60,
125.97, 124.72, 120.62, 109.21 78.81, 78.46, 78.25, 74.61, 74.48, 74.45,
72.35, 71.48, 71.35, 71.14, 70.31, 70.14, 69.34, 66.75, 66.56, 66.37, 61.32,
Ph-1,3,5-click-[G2.0] (22b): Reaction conditions and workup were as de-
scribed above, with 18 (0.2 g, 1.332 mmol, 1.0 equiv), 13 (3.172 g,
4.395 mmol, 3.3 equiv), DIPEA (33.0 mL, 0.1998 mmol, 0.15 equiv),
sodium ascorbate (79.2 mg, 0.3996 mmol, 0.3 equiv), and copper(II) sul-
fate pentahydrate (50.0 mg, 0.1998 mmol, 0.15 equiv) in THF/H2O
(14 mL). Purification by column chromatography (ethyl acetate/n-hexane
(6/1) and 5% MeOH in CH2Cl2) gave 22b (2.79 g, 91%). 1H NMR
(500 MHz, CDCl3, 258C): d=8.27 (s, 3H), 8.23–8.12 (m, 3H), 4.92 (m,
3H), 4.17 (m, 12H), 4.05 (m, 8H), 3.95 (m, 16H), 3.64 (m, 20H), 3.54–
3.47 (m, 46H), 1.33 (s, 36H; CH3), 1.26 ppm (s, 36H; CH3); 13C NMR
(125 MHz, CDCl3, 258C): d=146.53, 132.1, 122.0, 120.73, 109.4, 78.85,
78.51, 74.75, 74.70, 72.55, 71.65, 70.36, 69.42, 69.38, 66.4, 66.61, 61.08,
26.67, 25.29 ppm; ESI-TOF-MS found for
4799.5983): m/z (%): 1600.8726 [M+3H]3+
2422.7902 [M+2Na]2+
C
237H387N9O90 (calcd
,
2400.8223 [M+2H]2+
,
.
General procedure for the deprotection of the alcohol functionality: Ion-
exchange resin Dowex 50W was added to 1.0 equiv of acetal-protected
compound (20–23) dissolved in MeOH, and the mixture heated to reflux
for 12–24 h. After cooling, Dowex 50W was filtered off and washed with
a 5% solution of Et3N in MeOH, and concentration of the residue under
vacuum yielded 24–27.
26.83, 25.45 ppm; ESI-TOF-MS found for
C111H183N9O42 (calcd
2314.2461): m/z (%): 2315.2548 [M+H]+, 2337.2186 [M+Na]+, 2353.2322
[M+K]+.
Ph-1,3-click-[G1.0]-OH (24a): Reaction conditions and workup were as
described above, with 20a (1.06 g, 1.31 mmol) in MeOH (25 mL). Evapo-
ration of the solvent gave 24a (0.743 g, 1.13 mmol, 86.4%). 1H NMR
(250 MHz, CD3OD, 258C): d=8.53, 8.49, 8.45, 8.42 (brm, 2H), 8.22 (s,
1H), 7.76 (d, 2H, J=7.8 Hz), 7.44 (t, 1H, J=7.8 Hz), 5.01 (m, 2H) 4.77–
4.66 (m, 2H), 3.94 (m, 6H), 3.68 (m, 4H), 3.45 ppm (brm, 16H);
13C NMR (100 MHz, CD3OD, 258C): d=148.25, 148.08, 132.52, 132.45,
130.69, 126.38, 124.12, 124.08, 123.91, 122.65, 78.89, 78.81, 73.96, 73.83,
73.72, 72.69, 72.63, 72.31, 72.13, 72.04, 71.27, 64.27, 64.20, 62.49,
52.18 ppm; ESI-TOF-MS found for C28H44N6O12 (calcd 656.3017): m/z
(%): 657.3074 [M+H]+, 679.2891 [M+Na]+, 695.2601 [M+K]+.
Ph-1,3,5-click-[G3.0] (22c): Reaction conditions and workup were as de-
scribed above, with 18 (77.3 mg, 0.514 mmol, 1.0 equiv), 14 (2.5 g,
1.695 mmol, 3.3 equiv), DIPEA (25.4 mL, 0.154 mmol, 0.3 equiv), sodium
ascorbate (61.1 mg, 0.308 mmol, 0.6 equiv), and copper(II) sulfate penta-
hydrate (38.5 mg, 0.154 mmol, 0.3 equiv) in THF/H2O (14 mL). Purifica-
tion by column chromatography (ethyl acetate/n-hexane (10/1) and 5%
MeOH in CH2Cl2) gave 22c (1.02 g, 44%). 1H NMR (500 MHz, CDCl3,
258C): d=8.43–4.83 (brm, 6H), 4.88 (m, 3H), 4.17 (m, 24H), 4.03–3.97
(brm, 34H), 3.68–3.46 (brm, 164H), 1.36 (s, 72H; CH3), 1.26 ppm (s,
72H; CH3); 13C NMR (125 MHz, CDCl3, 258C): d=146.6, 129.30, 128.31,
123.14, 120.47, 109.25, 78.82, 78.50, 78.31, 74.64, 74.51, 72.37, 71.38, 70.28,
69.20, 69.16, 66.60 66.61, 26.69, 25.32 ppm; ESI-TOF-MS found for
Ph-1,3-click-[G2.0]-OH (24b): Reaction conditions and workup were as
described above, with 20b (1.77 g, 1.764 mmol) in MeOH (30 mL). Evap-
oration of the solvent gave 24b (1.395 g, 1.12 mmol, 99%). 1H NMR
(500 MHz, CD3OD, 258C): d=8.60, 8.58, 8.56 (m, 2H), 8.37 (s, 1H), 7.87
(d, 2H, J=8.0 Hz), 7.55 (t, 1H, J=7.8 Hz), 5.08 (m, 2H), 4.20–4.01
(brm, 8H), 3.74 (m, 12H), 3.65–3.40 ppm (brm, 48H); 13C NMR
(100 MHz, CD3OD, 258C): d=147.96, 147.90, 132.54, 130.80, 126.48,
123.84, 122.93, 122.83, 80.03, 79.67, 73.89, 72.83, 72.75, 72.47, 72.40, 72.13,
71.41, 70.47, 64.39, 63.26, 62.94 ppm; ESI-TOF-MS found for C52H92N6O28
(calcd 1248.5960): m/z (%): 1249.6002 [M+H]+, 1271.5827 [M+Na]+,
1287.5562 [M+K]+.
C
219H375N9O90 (calcd 4571.5044): m/z (%): 2286.2651 [M+2H]2+
2337.2186 [M+Na]+, 2353.2322 [M+K]+.
,
Ph-Ph-1,3,5-click-[G1.0] (23a): Reaction conditions and workup were as
described above, with 19 (0.2 g, 0.528 mmol, 1.0 equiv), 12 (0.602 g,
1.744 mmol, 3.3 equiv), DIPEA (39.2 mL, 0.238 mmol, 0.45 equiv),
sodium ascorbate (94.2 mg, 0.476 mmol, 0.9 equiv), and copper(II) sulfate
pentahydrate (59.4 mg, 0.238 mmol, 0.45 equiv) in THF/H2O (8 mL). Pu-
rification by column chromatography (ethyl acetate/n-hexane (3/1) and
5% MeOH in CH2Cl2) gave 23a (0.74 g, 99%). 1H NMR 500 MHz,
CDCl3, 258C): d=8.09 (t, 3H, J=9.8 Hz), 7.95 (d, 6H, J=8.2 Hz), 7.83
(s, 3H), 7.76 (d, 6H, J=8.3 Hz), 4.96 (m, 3H), 4.12 (m, 6H), 4.98 (m,
18H), 3.64 (m, 6H), 3.51 (m, 12H), 1.37 (s, 18H), 1.31 ppm (s, 18H);
13C NMR (125 MHz, CDCl3, 258C): d=146.86, 141.75, 140.41, 129.98,
127.57, 125.98, 124.74, 120.22, 109.43, 109.40, 74.45, 74.37, 72.39, 72.07,
70.03, 69.97, 66.12, 60.45, 26.59, 25.19 ppm; ESI-TOF-MS found for
C75H99N9O18 (calcd 1413.7108): m/z (%): 1414.7170 [M+H]+, 1436.6993
[M+Na]+, 1452.6667 [M+K]+.
Ph-1,3-click-[G3.0]-OH (24c): Reaction conditions and workup were as
described above, with 20c (0.483 g, 0.157 mmol) in MeOH (10 mL).
Evaporation of the solvent gave 24c (0.378 g, 0.155 mmol, 99%).
1H NMR (400 MHz, CD3OD, 258C): d=8.59 (m, 1H), 8.41 (m, 1H), 7.86
(d, 1H, J=7.3 Hz), 7.57 (t, 1H, J=7.7 Hz), 4.07 (m, 2H), 4.16 (m, 8H),
3.70–3.40 ppm (brm, 140H); 13C NMR (100 MHz, CD3OD, 258C): d=
147.78, 131.77, 129.10, 127.46, 123.09, 120.74, 80.56, 80.31, 79.83, 76.13,
73.97, 72.95, 72.43, 72.30, 72.20, 71.28, 71.07, 70.51, 67.56, 64.52,
63.43 ppm; ESI-TOF-MS found for C100H188N6O60 (calcd 2433.1844): m/z
(%): 1217.5989 [M+2H]2+, 1239.5814 [M+2Na]2+, 2434.1578 [M+H]+,
2456.1628 [M+Na]+.
Ph-Ph-1,3,5-click-[G2.0] (23b): Reaction conditions and workup were as
described above, with 19 (0.14 g, 0.37 mmol, 1.0 equiv), 13 (0.881 g,
1.221 mmol, 3.3 equiv), DIPEA (27.4 mL, 0.166 mmol, 0.45 equiv),
sodium ascorbate (65.9 mg, 0.333 mmol, 0.9 equiv), and copper(II) sulfate
pentahydrate (41.5 mg, 0.166 mmol, 0.45 equiv) in THF/H2O (8 mL). Pu-
rification by column chromatography (ethyl acetate/n-hexane (6/1) and
10% MeOH in CH2Cl2) gave 23b (0.80 g, 87%). 1H NMR (400 MHz,
CDCl3, 258C): d=8.096–8.05 (brm, 3H), 7.95 (d, 6H, J=7.8 Hz), 7.82 (s,
3H), 7.76 (d, 6H, J=8.0 Hz), 4.92 (m, 3H), 4.18 (m, 12H), 4.07 (m, 6H),
3.98 (m, 16H), 3.64–3.34 (brm, 68H), 1.35 (s, 36H), 1.29 ppm (s, 36H);
13C NMR (100 MHz, CDCl3, 258C): d=146.75, 146.64, 146.54, 141.80,
140.45, 130.17, 130.07, 129.97, 127.62, 125.97, 124.76, 120.38, 120.22,
109.28, 78.65, 78.34, 74.67, 74.50, 72.41, 71.62, 71.50, 70.21, 69.32, 66.60,
Ph-1,4-click-[G1.0]-OH (25a): Reaction conditions and workup were as
described above, with 21b (1.1 g, 1.35 mmol) in MeOH (25 mL). Evapo-
ration of the solvent gave 25b (0.774 g, 1.19 mmol, 88%). H1 NMR
(250 MHz, CD3OD, 258C): d=8.66, 8.61, 8.56, 8.54 (m, 2H), 7.98 (s, 4H),
5.14 (m, 2H), 4.77–4.66 (m, 2H), 4.07 (m, 6H), 3.81 (m, 4H), 3.58 ppm
(brm, 16H); 13C NMR (100 MHz, CD3OD, 258C): d=148.20, 148.04,
131.64, 127.19, 123.98, 123.94, 122.53, 83.47, 78.92, 78.84, 73.85, 73.73,
72.15, 71.29, 64.26, 62.51, 52.19 ppm; ESI-TOF-MS found for
C28H44N6O12 (calcd 656.3017): m/z (%): 657.3094 [M+H]+, 679.2906
[M+Na]+.
9212
www.chemeurj.org
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2008, 14, 9202 – 9214

Polyglycerol “Click” Dendrons
FULL PAPER
Ph-1,4-click-[G2.0]-OH (25b): Reaction conditions and workup were as
described above, with 21b (1.5 g, 0.955 mmol) in MeOH (25 mL). Evapo-
ration of the solvent gave 25b (1.13 g, 0.91 mmol, 95%). 1H NMR
(400 MHz, CD3OD, 258C): d=8.54, 8.53, 8.52, 8.50 (m, 2H), 7.95 (s, 4H),
5.04 (m, 2H), 4.18, 4.12 (m, 5H), 4.02, 3.98 (m, 3H), 3.71 (m, 10H), 3.63–
3.38 ppm (brm, 50H); 13C NMR (100 MHz, CD3OD, 258C): d=147.90,
131.66, 122.70, 80.09, 79.74, 73.92, 72.88, 72.79, 72.53, 72.46, 72.37, 72.19,
71.35, 70.52, 64.43, 63.29, 62.98 ppm; ESI-TOF-MS found for
C52H92N6O28 (calcd 1248.5960): m/z (%): 1249.6003 [M+H]+, 1271.5822
[M+Na]+, 1287.5535 [M+K]+.
62.49 ppm; ESI-TOF-MS found for C93H147N9O42 (calcd 2061.9644): m/z
(%): 2062.9786 [M+H]+, 1031.9927 [M+2H]2+
.
Ph-Ph-1,3,5-click-[G3.0]-OH (27c): Reaction conditions and workup
were as described above, with 23c (1.2 g, 0.25 mmol) in MeOH (25 mL).
1
Evaporation of the solvent gave 27c (0.89 g, 0.227 mmol, 91%). H NMR
(250 MHz, CD3OD, 258C): d=8.55 (s, 3H), 7.94 (m, 15H), 5.03 (m, 3H),
4.11 (m, 12H), 3.70–3.46 ppm (brm, 205H); 13C NMR (100 MHz,
CD3OD, 258C): d=1147.89, 143.21, 142.01, 131.31, 129.08, 127.45, 125.81,
123.07, 79.83, 73.97, 72.96, 72.21, 71.54, 71.28, 71.08, 64.53 ppm; ESI-
TOF-MS found for C165H291N9O90 (calcd 3838.8471): m/z (%): 1942.4156
[M+2Na]2+
.
Ph-1,4-click-[G3.0]-OH (25c): Reaction conditions and workup were as
described above, with 21c (0.526 g, 0.171 mmol) in MeOH (10 mL).
Evaporation of the solvent gave 25c (0.406 g, 0.167 mmol, 98%).
1H NMR (400 MHz, CD3OD, 258C): d=8.57 (s, 2H), 7.98 (s, 4H), 5.06
(m, 2H), 3.74 (m, 8H), 3.66–3.41 ppm (brm, 140H); 13C NMR
(67.5 MHz, CD3OD, 258C): d=147.85, 132.77, 130.97, 126.64, 123.89,
123.20, 80.56, 80.31, 80.08, 79.83, 73.96, 72.95, 72.43, 72.30, 72.19, 71.28,
71.07, 70.53, 64.52, 63.40 ppm; ESI-TOF-MS found for C100H188N6O60
Acknowledgements
(calcd 2433.1844): m/z (%): 1217.6011 [M+2H]2+
[M+H+Na]2+, 2434.2160 [M+H]+.
,
1228.5929
R.H. is indebted to the Bundesministerium für Forschung und Bildung
(BMBF) for a young scientist nanotechnology award and the German
Science Foundation (DFG) for funding within the SFBs 658 and 765.
M.W. and R.H. thank Dr. W. Dilla from Solvay Chemicals GmbH for the
generous gift of triglycerol. The authors thank W. Münch for his help
with HPLC purification.
Ph-1,3,5-click-[G1.0]-OH (26a): Reaction conditions and workup were as
described above, with 22a (1.38 g, 1.16 mmol) in MeOH (25 mL). Evapo-
ration of the solvent gave 26a (1.05 g, 1.1 mmol, 95.3%). 1H NMR
(250 MHz, CD3OD, 258C): d=8.66, 8.61, 8.56, 8.54 (m, 3H), 8.28, 8.27
(m, 3H), 5.10 (m, 3H), 4.76–4.58 (brm, 2H), 4.06 (m, 5H), 4.00 (m, 4H),
3.78 (m, 7H), 3.62–3.48 ppm (m, 24H); 13C NMR (100 MHz, CD3OD,
258C): d=147.77, 133.34, 123.38, 122.98, 83.49, 78.93, 78.85, 74.02, 73.89,
73.79, 72.75, 72.68, 72.35, 72.17, 72.08, 71.30, 64.34 62.56 ppm; ESI-TOF-
MS found for C39H63N9O18 (calcd 945.4291): m/z (%): 946.4364 [M+H]+,
968.4183 [M+Na]+, 984.3923 [M+K]+.
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Ph-1,3,5-click-[G2.0]-OH (26b): Reaction conditions and workup were
as described above, with 22b (1.62 g, 0.955 mmol) in MeOH (25 mL).
Evaporation of the solvent gave 26b (1.07 g, 84%). 1H NMR (250 MHz,
CD3OD, 258C): d=8.65, 8.64 (m, 3H), 8.33 (m, 3H), 5.06 (m, 3H), 4.15
(m, 6H), 3.97 (m, 6H), 3.70 (m, 16H) 3.61–3.47 ppm (m, 74H); 13C NMR
(100 MHz, CD3OD, 258C): d=147.71, 147.65, 133.44, 123.53, 123.30,
123.21, 80.12, 79.72, 79.66, 73.95, 72.88, 72.80, 72.55, 72.47, 72.37, 72.20,
71.49, 64.43, 63.43, 63.11 ppm; ESI-TOF-MS found for C75H135N9O42
(calcd 1833.8705): m/z (%): 1834.8782 [M+H]+, 1856.8598 [M+Na]+.
Ph-1,3,5-click-[G3.0]-OH (26c): Reaction conditions and workup were as
described above, with 22c (0.8 g, 0.175 mmol) in MeOH (25 mL). Evapo-
ration of the solvent gave 26c (0.589 g, 0.16 mmol, 92%). 1H NMR
(400 MHz, CD3OD, 258C): d=8.68 (brs, 3H), 8.02, 7.99 (m, 3H), 5.10
(m, 3H), 4.20 (m, 12H), 3.77–3.54 ppm (brm, 214H); 13C NMR
(125 MHz, CD3OD, 258C): d=146.89, 133.27, 130.15, 129.61, 125.24,
124.98 123.97, 123.57, 83.89, 83.09, 80.53, 80.28, 79.82, 76.10, 73.95, 72.93,
72.41, 72.29, 72.17, 71.24, 71.05, 70.45, 64.50, 63.39 ppm; ESI-TOF-MS
found for
[M+2H]2+
C150H283N9O90 (calcd 3650.7845): m/z (%): 1826.3985
.
Ph-Ph-1,3,5-click-[G1.0]-OH (27a): Reaction conditions and workup
were as described above, with 23a (0.62 g, 0.438 mmol) in MeOH
(15 mL). Evaporation of the solvent gave 27a (0.446 g, 0.38 mmol, 87%).
1H NMR (250 MHz, CD3OD, 258C): d=8.45 (s, 3H), 7.86 (d, 6H, J=
8.2 Hz), 7.84 (s, 3H), 7.67 (d, 6H, J=8.3 Hz), 5.01 (m, 3H), 3.96 (m,
12H), 3.72 (m, 8H), 3.58–3.40 ppm (m, 22H); 13C NMR (100 MHz,
CD3OD, 258C): d=148.18, 142.93, 141.79, 131.08, 128.79, 127.24, 125.59,
122.53, 73.90, 73.77, 72.20, 72.11, 71.33, 64.31, 62.50 ppm; ESI-TOF-MS
found for C57H75N9O18 (calcd 1173.5230): m/z (%): 1174.5330 [M+H]+,
1196.5147 [M+Na]+, 1212,4864 [M+K]+.
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d=148.01, 143.13, 141.87, 131.20, 128.94, 127.35, 125.73, 122.68, 80.10,
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Received: May 9, 2008
Published online: September 3, 2008
9214
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Chem. Eur. J. 2008, 14, 9202 – 9214