New approaches towards monoamino polyglycerol dendrons and dendritic triblock amphiphiles

Article abstract of DOI:10.1002/ejoc.200700683

In order to improve the water solubility of nonpolar compounds such as drugs or dyes, new amphiphilic molecules are needed. In this paper we describe a new class of triblock amphiphiles that we have synthesized by a straightforward convergent approach. These amphiphiles each consist of a nonpolar biphenyl core and a polar shell based on various generations of monoamino polyglycerol dendrons, coupled to the core through amide linkages (1). For the synthesis of these monoamino dendrons we applied a simple iterative two-step process based on allylation of an alcohol group and catalytic dihydroxylation. As starting materials, D,L-serine/serinol and - in a second, similar pathway - commercially available triglycerol were used. The transport behavior of these defined triblock amphiphiles was then investigated with the nonpolar dye Nile Red in water. Wiley-VCH Verlag GmbH & Co. KGaA, 2008.

Full text of DOI:10.1002/ejoc.200700683

FULL PAPER
DOI: 10.1002/ejoc.200700683
New Approaches Towards Monoamino Polyglycerol Dendrons and Dendritic
Triblock Amphiphiles
Monika Wyszogrodzka,[a] Katrin Möws,[b] Stefan Kamlage,[a] Joanna Wodzin´ska,[a]
Bernd Plietker,*[b] and Rainer Haag*[a,b]
Keywords: Polyglycerol dendrimers / Amphiphiles / Nile Red / Fluorescence / UV/Vis spectroscopy
In order to improve the water solubility of nonpolar com-
pounds such as drugs or dyes, new amphiphilic molecules
are needed. In this paper we describe a new class of triblock
amphiphiles that we have synthesized by a straightforward
convergent approach. These amphiphiles each consist of a
nonpolar biphenyl core and a polar shell based on various
generations of monoamino polyglycerol dendrons, coupled to
the core through amide linkages (1). For the synthesis of
these monoamino dendrons we applied a simple iterative
two-step process based on allylation of an alcohol group and
catalytic dihydroxylation. As starting materials, -serine/
serinol and – in a second, similar pathway – commercially
available triglycerol were used. The transport behavior of
these defined triblock amphiphiles was then investigated
with the nonpolar dye Nile Red in water.
D,L
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2008)
Introduction
In view of these results, we decided to design dendritic tri-
block amphiphiles consisting of biphenyl cores with two
carboxylate groups at their 4,4Ј-positions and shells based
on monoamino polyglycerol dendrons (Figure 1). Attractive
overlapping through π–π stacking between the aromatic
moieties in host and guest made up the rationale for ex-
pecting good transport capacities for compounds with
structures such as that of Nile Red (2). The biocompat-
ibility properties of the aliphatic polyethers, in particular,
the high biocompatibility of the polyglycerol oligomers, e.g.,
Dendrimers[1] are a unique class of polymers, which are
different from all the other macromolecules because of their
globular shape, resulting from their highly ordered, per-
fectly branched architectures and their monodisperse struc-
tures.[2] The molecular weight, shape, size and chemical
functionality of dendrimers can be controlled through the
synthetic methods used for their preparation. So far, two
complementary general approaches – divergent and conver-
gent – have been used.[3] The unique properties of dendri-
mers and dendrons allow for their application as a new scaf-
fold type in drug and dye solubilization.[4]
Among the various polymeric drug carriers known to-
day,[5] dendritic polymers based on polyglycerol (PG), with
their defined core-shell-type architectures, have shown good
transport capacities for poorly water-soluble drugs. In pre-
vious studies, paclitaxel (PTX) was solubilized in water
through the use of polyglycerol dendrimers[6] of generations
[G4] and [G5].[7] Recently, we have shown that hyper-
branched polyglycerol with a biphenyl-functionalized core
can be used as a nanocarrier for hydrophobic drugs.[8]
Thanks to the π–π interactions between nimodipine or py-
rene and the biphenyl moiety, high transport capacities for
these systems were observed.
[a] Institut für Chemie und Biochemie, Freie Universität Berlin,
Takustr. 3, 14195 Berlin, Germany
Fax: +49-30-838-53357
E-mail: haag@chemie.fu-berlin.de
[b] Organische Chemie, Fachbereich Chemie, Universität Dort-
mund,
Otto-Hahn-Str. 6, 44221 Dortmund, Germany
Fax: +49-231-755-3884
E-mail: plietker@pop.uni-dortmund.de
Figure 1. Designed triblock architecture of the amphiphiles with
outer polyglycerol blocks and a central biphenyl unit.
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B. Plietker, R. Haag et al.
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food and pharma additives[9] and dendritic polymers[10], are
scientifically very interesting for evaluation of new amphi-
philic moieties based on polyglycerol dendrons.
Results and Discussion
Design of Dendritic Triblock Amphiphiles and Selection of
Dyes
The incorporation of focal primary amino units into poly-
glycerol-based dendrons would allow a modular approach
for the generation of various dendritic architectures
through amide linkages (1). Depending on the molecular
geometry of the guest molecule it should then be possible
to use the biphenyl core and various sizes of the shell to
influence the environment of Nile Red (2).
Scheme 1. Preparation of the starting material Bn2N-[G0]-OH for
the construction of monoamino polyglycerol dendrons.
Nile Red, an environmentally sensitive fluorescent dye,
was chosen as model compound (Figure 1). This hydro-
phobic solvatochromic dye is used as a fluorescent probe
in many biological and medical studies for localizing and
quantitating lipids,[11] identifying hydrophobic sites on the
surface of proteins,[12] and detecting ligand binding to en-
zymes.[13] It is known that the fluorescence of Nile Red
strongly depends on the polarity of the environment, being
redshifted and strongly quenched in polar solvents and ap-
proaching a maximum blueshift and intensity in apolar sol-
vents/environment.[14] The remarkable sensitivity of Nile
Red has also been beneficial in studies of the local polarity
of bolaamphihiles[15] and micelles[16] and of interactions
with cyclodextrins.[17] Small changes in the organization of
the surfactants in the solvent system could be monitored by
Nile Red,[16c] while the specific properties of Nile Red could
also be used to characterize surfactant/amphiphiles self-as-
sembly processes and phase behavior.
Synthesis of Bifunctional Glycerol Dendrons from
Serine/Serinol
D,L-
To synthesize the starter Bn2N-[G0]-OH[21] (4), commer-
cially available serinol (2-aminopropane-1,3-diol) (3) was
treated with benzyl bromide in the presence of K2CO3 in
ethanol. In spite of a one-step reaction and a very good
yield with the use of serinol as the starting material, we
decided to use the much cheaper ,-serine (5) as starting
material for the up-scaling of the dendrimer synthesis. Pro-
tection of the amino functionality of ,-serine was carried
out by using the same conditions as described for serinol.
Because of partial ester formation, treatment with aqueous
NaOH solution (20%) at 80 °C for 3 h followed by addition
of acid was necessary. The resulting N,NЈ-dibenzylserine
was transformed into the corresponding diol 4 by reduction
with NaBH4 and I2 in THF in high yield (Scheme 1).[22]
Compound Bn2N-[G0.5]-allyl (7; Scheme 2) was ob-
tained in very good yield (80%) by treatment of 4 with allyl
Synthesis of Bifunctional Glycerol Dendrons
For the synthesis of bifunctional glycerol dendrons we bromide and aqueous NaOH (50%) in the presence of a
chose a divergent growth approach based on the application phase-transfer catalyst such as tetrabutylammonium iodide
of a reaction sequence similar to the one we had recently (TBAI). Higher generations (compounds 9 and 11) were
developed for the synthesis of glycerol dendrimers.[6,18] We synthesized by this method in 49% and 79% yields, respec-
selected a simple iterative two-step process based on al- tively. For the dihydroxylation an optimized Upjohn pro-
lylation[19] of an alcohol functionality under phase-transfer cess, with N-methylmorpholine N-oxide as a reoxidizing
conditions and subsequent catalytic dihydroxylation[20] of agent, proved to be successful. In the course of optimization
the allylic double bond to obtain the desired generations it was found that as little as 0.25 mol-% K2OsO4 per double
[G1.0–G3.0] of monoamino glycerol dendrons. As starting bond was sufficient to provide the dendritic polyols in very
materials we used either 2-aminopropane-1,3-diol (3)/,- good yields. The NMR spectra of the crude products
serine (5) (Scheme 1) or, to reduce the number of reaction showed quantitative conversion of the allyl groups for every
steps, commercially available triglycerol (13; Scheme 3). In generation. The purification of Bn2N-[G1.0]-OH (8), Bn2N-
both cases it was necessary to protect the amino function- [G2.0]-OH (10) and Bn2N-[G3.0]-OH (12) was achieved by
ality, which was achieved either by benzyl protection or by filtration (silica gel, ethanol) and size exclusion column
using an azide as precursor.
chromatography (Sephadex, methanol).
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Monoamino Polyglycerol Dendrons and Dendritic Triblock Amphiphiles
Scheme 2. Reaction sequence for the construction of polyglycerol dendrons with benzyl protection. Reagents and conditions: a) allyl
bromide, 50% NaOH, TBAI, 40 °C, 18 h; b) 1 mol-% K2OsO4, NMO, acetone/water/tert-butyl alcohol, 40 °C, 18 h.
Synthesis of Bifunctional Glycerol Dendrons from
Triglycerol
For an alternative approach to bifunctional dendrons
with amine groups as focal points, and to reduce the
number of steps needed to generate an H2N-[G3.0]-OH
(23), we used triglycerol (13) as a building block. In view of
the high stability of the azide functionality under acidic,
basic and oxidative conditions we decided to use it as a
precursor for the amino functionality[23] (Scheme 3). We
once again applied a reaction sequence based on allylation
of the alcohol under phase-transfer conditions and catalytic
dihydroxylation of the allylic double bonds (Scheme 4). The
commercially available triglycerol (13) was protected with
acetone dimethylacetal on the terminal diols, the corre-
sponding acetal-protected triglycerol 14 being obtained in
78% yield.[18]
Since triglycerol contains over 20% other oligomers (e.g.,
diglycerol, tetraglycerol etc.) as impurities, purification by
flash column chromatography was necessary. The second-
ary free hydroxy group of compound 14 was converted into
the corresponding mesylate, which was treated without fur-
ther purification with sodium azide to give N3-[G1.0] (15)
in 96% yield over two steps. The acetal protection was re-
moved in almost quantitative yield by stirring with an acidic
ion-exchange resin in methanol. The resulting N3-[G1.0]-
OH (16) was treated with allyl bromide to give N3-[G1.5]-
allyl (17) in 85–94% yield (Scheme 4). Catalytic dihydrox- the construction of monoamino polyglycerol dendrons.
Scheme 3. Preparation of the starting material N3-[G1.0]-OH for
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B. Plietker, R. Haag et al.
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Scheme 4. Reaction sequence for the construction of polyglycerol dendrons with azide precursor. Reagents and conditions: a) allyl bro-
mide, 50% NaOH, TBAI, 40 °C, 18 h; b) AD-mix-α, water/tert-butyl alcohol, 0 °C, 24 h; c) 1 mol-% K2OsO4, NMO, citric acid, acetone/
water/tert-butyl alcohol, 40 °C, 24 h.
ylation of the double bond with osmium tetroxide and Synthesis of the Dendritic Triblock Amphiphiles
NMO was not successful, which was probably due to de-
The resulting polyols 21–23 were attached to the 4,4Ј-
biphenyldicarboxylic acid core to give the desired triblock
amphiphiles 25–27 by DCC coupling. (Figure 2 and
Table 1). The carboxylic acid groups were first activated
with HOBt (1-hydroxybenzotriazole) or NHS (N-hydroxy-
succinimide) and a catalytic amount of DMAP, followed by
slow addition of DMF solutions of the monoamino poly-
activation of the catalyst by the azide functionality.[24]
Therefore, we decided to use AD-mix-α (or AD-mix-β) ac-
cording to the procedure described by Sharpless et al.,[20c]
which led to the formation of new glycerol units on every
available allyl functionality in high yield. However, no pro-
moted stereoselectivity was observed in this reaction. Repe-
tition of the allylation and dihydroxylation of the double
bond with osmium tetroxide and NMO resulted in N3-
[G3.0]-OH (20).
All generations of protected dendrons (from [G1.0] to
[G3.0]) were converted into the corresponding monoamino
glycerol dendrons 8, 10 and 12 by a simple hydrogenation
procedure with 10% Pd/C (Scheme 5). With benzyl-pro-
tected dendrons the reaction was performed under 5 bar of
H2 pressure, but in the cases of compounds 10 and 12 the
reactions were still incomplete after 18 h (as determined by
1H NMR), and so further quantities of fresh catalyst were
used. Conversion from the azide functionalities to primary
amines, on the other hand, was complete under a lower
hydrogen pressure and without any extra amount of the cat-
alyst after 24 h. In all cases, purification of 21–23 was per-
formed by simple filtration through Celite® pads, yielding
pure monoamino dendrons in 85–99% yields.
Figure 2. Attachment of the dendrons to the biphenyl core to form
triblock amphiphiles.
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Monoamino Polyglycerol Dendrons and Dendritic Triblock Amphiphiles
Scheme 5. Monoamino polyglycerol dendrons: a) 10% Pd/C, MeOH, 5 bar H2, 24 h; b) twice: 10% Pd/C, MeOH, 5 bar H2, 24 h; c) 10%
Pd/C, MeOH, 1.1 bar H2, 24 h.
glycerol dendrons. Purification of these dendritic architec- traction. Nile Red in powder was added, and the suspen-
tures was performed by reversed-phase HPLC (water/meth- sions were stirred vigorously in water.
anol, 1:1), as well as by dialysis in methanol. Because of the
relatively low yields, an alternative coupling method using
2-ethoxy-N-(ethoxycarbonyl)-1,2-dihydroquinoline (EEDQ)
by the procedure of Heagy et al.,[25] was tried, but the ob-
tained results were comparable.
The result revealed a strong redshift of the absorption
band for the Nile Red with the [G1] dendron complex, with
λmax = 620 nm, and a strong blueshift for it in the [G2]
dendron complex, with λmax = 462 nm (Figure 3). The first
shift corresponds to a highly polar environment, such as
the PG groups, surrounding the Nile Red. The latter value
for Nile Red absorption indicates a highly nonpolar envi-
ronment of the dye, such as the biphenyl core. The dye/
polymer transport ratios were calculated for the highest
tested concentration of solutes (10.0 gdm–3), and were
1:292 and 1:4960 for the [G1] and [G2] dendrons, respec-
tively (Scheme 6). The results are strongly opposed to the
expected transport capacities. The encapsulation capacity
was expected to increase with each dendrimer generation,
while the obtained results indicate the opposite tendency.
This behavior could be explained by aggregation of the tri-
Table 1. Attachment of the dendrons to the biphenyl core.
Product
Generation
Coupling reagent
Yield (%)[a]
25
26
27
[G1]
[G2]
[G3]
3 equiv. HOBt
3 equiv. HOBt
3 equiv. NHS
33
29
24
[a] After purification by RP-HPLC (water/methanol, 1:1).
Transport Behavior of the Polyglycerol-Based Triblock
Amphiphiles
The dye transport capacities of the obtained [G1] and block amphiphiles, rather than a unimolecular transport be-
[G2] dendritic amphiphiles were tested by solid–liquid ex- havior as was initially intended.
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B. Plietker, R. Haag et al.
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Scheme 6. Polyglycerol-based triblock amphiphiles.
introduced. Although some problems with the scale-up ap-
peared, bifunctional dendrons up to H2N-[G3.0]-OH (23)
were produced in good yields. In the dihydroxylation reac-
tions, replacement of NMO by citric acid/H2O2 as co-oxi-
dant resulted in almost colorless products.
Our main goal was to achieve an easy route to a variety
of well-defined monoamino polyglycerol dendrons, and it
was demonstrated that application of different coupling
procedures to a biphenyl core results in a new type of tri-
block amphiphiles based on amide linkages. The transport
properties of these macromolecules were tested with the
nonpolar guest Nile Red. Also, we have shown that with
higher dendron generations the amount of encapsulated
Nile Red unexpectedly decreased. However, because the
complexes formed between Nile Red (2) and the dendritic
polyglycerol derivatives 25–26 were lower than 1:1 composi-
tions in all cases, the formation of larger aggregates is likely
to occur. Further studies will focus on the modification of
the core unit in this modular approach and on the size de-
Figure 3. UV absorption of Nile Red encapsulated in [G1] and [G2]
dendrimers.
Conclusions
Two new synthetic pathways for the synthesis of termination of this new class of dendritic triblock amphi-
monoamino polyglycerol dendrons have been successfully philes.
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Monoamino Polyglycerol Dendrons and Dendritic Triblock Amphiphiles
Reduction of 6 to Bn2N-[G0]-OH (4): The protected ,-serine
(5.47 g, 19.2 mmol) and sodium borohydride (1.72 g, 2.4 equiv.)
were dissolved in dry THF in a three-neck round-bottomed flask
with mechanical stirrer, condenser and dropping funnel. The mix-
ture was cooled to 0 °C (ice/water bath), and iodine (4.87 g,
1.0 equiv.), dissolved in dry THF (15 mL), was added dropwise
with vigorous stirring. Next the mixture was stirred under reflux
conditions for 18 h. The solution was cooled to room temperature,
and methanol was added until the solution became clear. After
30 min of stirring, the solvent was removed by rotary evaporation
at aspirator pressure, and the residual white paste was dissolved in
aqueous KOH (20%, 50 mL). The mixture was stirred at 75 °C for
1 h and then extracted with chloroform after cooling down to room
temperature. The organic layers were combined, dried with MgSO4,
filtered and concentrated by rotary evaporation to provide the
product in 92% yield.
Experimental Section
General Remarks: Reactions requiring dry conditions were carried
out under argon. Dry and analytical-grade solvents were purchased
from Acros and used as received. H and 13C NMR spectra were
1
recorded with Bruker DRX 400 and DRX 500 spectrometers op-
erating at 300, 400, 500 MHz and 100.5, 125.7 MHz, respectively.
The spectra were calibrated on the solvent peak (CDCl3: δ =
7.26 ppm for 1H and δ = 77.0 ppm for 13C. CD3OD: δ = 4.84 ppm
1
for H and δ = 49.05 ppm for 13C. [D6]acetone: δ = 2.05 ppm for
1H and δ = 30.83 ppm for 13C). Flash chromatography was per-
formed on silica gel 60 (230–400 mesh) with head pressure supplied
by compressed air. Infrared spectra (IR) were recorded as thin films
between KBr or CaF2 plates. The instrument used was a Bruker
IFS 66 FT-IR spectrophotometer. For ESI measurements
a
TSQ 7000 (Finnigan Mat) instrument and for MALDI measure-
ments a Voyager-DE PRO BioSpectrometry Workstation were
used. High-resolution mass spectra were recorded with a JEOL
JMS-SX-102A spectrometer. HPLC was carried out with a Knauer
HPLC (pump K-120) with use of a Knauer RI-detector K-2401
and a Eurosphere 100-5C-18 column. UV measurements were car-
ried out with a Specord S100 UV/Vis spectrometer (Analytik Jena)
at 25 °C.
General Procedure for the Allylation of Alcohol Groups: Allyl bro-
mide (2.5–5 equiv. per OH group) was added to a solution of the
alcohol and TBAI (10–20 mol-%) as phase-transfer catalyst in
aqueous NaOH (50% w/v, 2.5–5 equiv. per OH group). The reac-
tion mixture was then stirred at 40–50 °C for 24–72 h. After ad-
dition of n-hexane and sat. NH4Cl, the organic phase was sepa-
rated, washed with water, dried with Na2SO4 and concentrated un-
der vacuum. The crude product was further purified by column
chromatography on silica gel to give the products as colorless oils
(in the case of allylation of the azide derivatives, smaller amounts
of reagents were used – 2.5 equiv. per OH group of allyl bromide,
50% NaOH and 10 mol-% of TBAI).
Benzyl Protection of 2-Aminopropane-1,3-diol – Bn2N-[G0]-OH (4):
2-Aminopropane-1,3-diol (3.0 g, 32.9 mmol) and anhydrous potas-
sium carbonate (14.3 g, 0.104 mol, 3.15 equiv.) were suspended in
ethanol (120 mL). The mixture was stirred mechanically, and ben-
zyl bromide (16.9 g, 11.8 mL, 98.8 mmol, 3.0 equiv.) was added
dropwise over 30 min. After the mixture had been stirred at reflux
for 3 h, solids were separated by filtration (EtOAc was used for
washings), and volatiles were removed under reduced pressure. The
residue was dissolved in EtOAc, and the solution was washed with
water, aqueous NaHCO3 and brine. After drying with anhydrous
Na2SO4 and removal of solvent under reduced pressure, the crude
mixture was purified by flash chromatography on silica gel (n-hex-
ane/ethyl acetate, 2:1, followed by ethyl acetate/n-hexane, 4:1), giv-
ing a clean product (8.4 g, 94%). 1H NMR (250 MHz, CDCl3,
25 °C): δ = 7.36–7.20 (m, 10 H, Ph-H), 3.74 (s, 4 H), 3.69 (dd, J =
10.8, 7.6 Hz, 2 H), 3.59 (dd, J = 16.2, 10.8, 5.9 Hz, 2 H), 2.99 (m,
3 H, CH, OH) ppm. 13C NMR (67.5 MHz, CDCl3, 25 °C): δ =
Bn2N-[G0.5]-allyl (7): Reaction conditions and workup were as de-
scribed above, with benzylated serinol 4 (2.867 g, 10.57 mmol),
TBAI (0.78 g, 2.11 mmol, 20 mol-%), NaOH (50%, 8.5 mL,
0.11 mol, 5 equiv. per OH group) and allyl bromide (9.15 mL,
0.11 mol, 5 equiv. per OH group). Purification was by flash
chromatography on silica gel (n-hexane/ethyl acetate 10:1), provid-
ing title compound 5 (2.97 g, 8.46 mmol, 80%) as a colorless oil.
The residue was chromatographed on silica gel with n-hexane/ethyl
1
acetate 10:1. H NMR (400 MHz, CDCl3, 25 °C): δ = 7.38 (d, J =
7.3 Hz, 4 H), 7.26 (m, 4 H) 7.18 (m, 2 H), 5.89 (m, 2 H), 5.25/5.15
(2ϫdd, J = 17.9/10.5 Hz, 4 H), 3.93 (d., J = 5.5 Hz, 4 H), 3.79 (s,
4 H), 3.62 (m, 4 H), 3.11 (m, 1 H) ppm. 13C NMR (125 MHz,
CDCl3, 25 °C): δ = 140.9, 138.2,135.2, 128.8, 126.8, 116.5, 72.1,
139.2, 128.8, 128.40, 127.38, 59.8, 59.7, 53.9 ppm. IR: ν = 3284,
˜
3026, 2927, 2853, 1493, 1452, 743 cm–1. QFT ESI MS: calcd. for
C17H21NO2 271.1572; found 272.1636 [M + H]+.
69.6, 56.6, 56.4 ppm. IR: ν = 3062, 3063, 2852, 1494, 1453, 1361,
˜
1099, 746, 699 cm–1. HR MS: calcd. for C23H29NO2 351.2198;
found 351.2209.
Benzyl Protection of
D,L-Serine (6): ,-Serine (30.0 g, 0.28 mol)
and tetrabutylammonium iodide (TBAI, 10.6 g, 10 mol-%) were
dissolved in a solution of potassium hydroxide (39% KOH aq.,
300 mL) and EtOH (300 mL). Benzyl chloride (197 mL, 6.0 equiv.)
was added dropwise, and the mixture was stirred under reflux con-
ditions for 1 h. Next, after the mixture had cooled to 40 °C, KOH
(11.7 g) was added, and the mixture was stirred under reflux condi-
tions for 1 h. The mixture was cooled down to room temperature,
and water was added to dissolve the white precipitate. The aqueous
layer was extracted with toluene, and solvent was removed by ro-
tary evaporation at aspirator pressure. After the pH value had been
adjusted to 5 with acetic acid, the mixture was left overnight for
crystallization, yielding white crystals (61 g, 75%); m.p. 133–
134 °C. 1H NMR (400 MHz, CD3OD, 25 °C): δ = 7.34–7.44 (m, 10
H, Aryl-H), 4.18 (m, 4 H, Bn-CH2), 4.08 (dd, J = 11.8, 5.8 Hz, 1
H, CH2), 3.96 (dd, J = 11.8, 8.0 Hz, 1 H, CH2), 3.67 (dd, J = 7.8,
Bn2N-[G1.5]-allyl (9): Reaction conditions and workup were as de-
scribed above, with the unpurified alcohol 8 (2.845 mmol), TBAI
(0.21 g, 0.57 mmol, 20 mol-%), NaOH (50%, 6.6 mL, 56.9 mmol,
5 equiv. per OH group) and allyl bromide (4.9 mL, 56.9 mmol,
5 equiv. per OH group). Purification was by flash chromatography
on silica gel (n-hexane/ethyl acetate, 6:1), providing title compound
1
6 (0.8 g, 1.38 mmol, 49%) as a colorless oil. H NMR (400 MHz,
CDCl3, 25 °C): δ = 7.15–7.37 (m, 10 H), 5.89 (m, 4 H), 5.20 (m, 8
H), 4.12 (m, 4 H), 3.98 (m, 4 H), 3.77 (s, 4 H), 3.46–3.65 (m, 15
H), 3.07 (m, 1 H) ppm. 13C NMR (100 MHz, CDCl3, 25 °C): δ =
140.9, 135.4, 134.9, 128.8, 128.3, 126.8, 117.1, 117.0, 77.3, 72.5,
71.5, 70.9, 70.8, 70.5, 55.3, 56.6 ppm. IR: ν = 3081, 3025, 2862,
˜
1494, 1453, 1361, 1108, 746, 699 cm–1. HR MS: calcd. for
C35H49NO6 579.3560; found 579.3537.
5.8 Hz, 1 H, CH) ppm. 13C NMR (100 MHz, CD3OD, 25 °C): δ = Bn2N-[G2.5]-allyl (11): Reaction conditions and workup were as
172.3, 136.4, 130.9, 130.0, 129.6, 65.7, 60.5, 56.6 ppm. IR: ν = 3410, described above, with the unpurified alcohol 10 (0.5 mmol), TBAI
˜
3171, 1613, 1497, 1454, 758, 702 cm–1. HR FAB MS: calcd. for
C17H19NO3 285.1365; found 285.1421.
(37 mg, 0.1 mmol, 20 mol-%), NaOH (50%, 1.6 mL, 20 mmol,
5 equiv. per OH group) and allyl bromide (1.73 mL, 20 mmol,
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FULL PAPER
5 equiv. per OH group). After 24 h, further allyl bromide (0.5 mL,
12 equiv.) was added and stirring was continued for an additional
36 h. Purification was by flash chromatography on silica gel (n-
hexane/ethyl acetate, 4:1), providing title compound 7 (0.411 g,
0.479 mmol, 79%) as a colorless oil. 1H NMR (400 MHz, CD3OD,
ethyl acetate, 1:4) and characterized. 1H NMR (400 MHz, CD3OD,
25 °C): δ = 7.16–7.39 (m, 10 H), 3.39–3.77 (m, 18 H), 3.05 (m, 1
H) ppm. 13C NMR (125 MHz, CD3OD, 25 °C): δ = 142.0, 141.8,
129.9, 129.8, 129.2, 129.1, 127.9, 127.8, 73.7, 73.6, 72.3 (2ϫ), 71.5,
70.9, 70.8, 64.7, 64.6, 61.4, 60.0, 59.9, 58.1, 56.1, 55.8 ppm. IR: ν
˜
25 °C): δ = 7.04–7.19 (m, 10 H), 5.90 (m, 7 H), 5.20 (m, 15 H), = 3385, 2928, 2873, 1494, 1453, 1387, 1100, 1072, 1043, 749,
4.12 (m, 8 H), 3.98 (m, 8 H), 3.49–3.79 (m, 35 H), 3.04 (m, 1 H)
ppm. 13C NMR (125 MHz, CD3OD, 25 °C): δ = 142.7, 142.1, 136.6
(2ϫ), 136.2, 136.1, 129.8, 129.2, 127.8, 117.2, 117.1, 117.0 (2ϫ),
80.0, 78.9, 78.6, 73.3, 72.7, 72.5, 72.2 (2ϫ), 71.8, 71.3 (2ϫ), 71.2,
700 cm–1. HR MS: calcd. for C23H33NO6 419.2308; found
420.2393.
Bn2N-[G2.0]-OH (10): Reaction conditions and workup were as de-
scribed above, with the allyl ether 9 (600 mg, 1.03 mmol), NMO
(846 mg, 613 mg, 4.532 mmol, 4.4 equiv.) and K2OsO4 (3.8 mg,
0.01 mmol, 1 mol-%) in acetone/distilled water/tert-butyl alcohol
(6.6 mL) with stirring for 12 h. Dialysis in methanol gave a brown
oil (428 mg, 0.60 mmol, 58%). 1H NMR (400 MHz, CD3OD,
25 °C): δ = 7.18–7.40 (m, 10 H, Aryl-H), 3.50–3.78 (m, 42 H), 3.03
(m, 1 H) ppm. 13C NMR (125 MHz, CD3OD, 25 °C): δ = 142.0,
58.1, 56.3 ppm. IR: ν = 2980, 2865, 1494, 1454, 1350, 1108, 924,
˜
747, 700 cm–1. HR MS: calcd. for C59H89NO14 1035.6283; found
1036.6395 [M + H]+. C59H89NO14 (1036.34): calcd. C 68.4, H 8.7,
N 1.4; found C 68.1, H 8.9, N 1.4.
N3-[G1.5]-allyl (17): Reaction conditions and workup were as de-
scribed above, with the alcohol 16 (13.2 g, 49.76 mmol), TBAI
(1.84 g, 19.9 mmol, 10 mol-%), NaOH (50%, 39.8 mL, 0.498 mol, 129.8, 129.2, 127.8, 80.0, 79.9, 75.0, 74.0, 73.0, 72.9, 72.6, 72.5,
2.5 equiv. per OH group) and allyl bromide (43.1 mL, 0.498 mol,
2.5 equiv. per OH group). Purification was by flash chromatog-
raphy on silica gel (n-hexane/ethyl acetate, 4:1), providing title com-
pound 9 (17.36 g, 40.8 mmol, 82%) as a colorless oil. 1H NMR
(500 MHz, CDCl3, 25 °C): δ = 5.89 (tddd, J = 17.2, 10.4, 9.6,
5.6 Hz, 4 H), 5.26 (qdd, J = 17.2, 6.0, 1.6 Hz, 4 H), 5.16 (dddd, J
= 10.4, 6.4, 3.0, 1.3 Hz, 4 H), 4.13 (ddd, J = 5.7, 2.6, 1.3 Hz, 4 H),
3.98 (td, J = 5.6, 1.3 Hz, 4 H), 3.70–3.51 (m, 15 H) ppm. 13C NMR
(125 MHz, CDCl3, 25 °C): δ = 135.0, 134.6, 116.93, 116.88, 76.9,
72.4, 72.2, 72.1, 71.6 (2ϫ), 64.5 (2ϫ), 58.0, 56.2 ppm. IR: ν = 3385,
˜
2920, 2876, 1494, 1454, 1362, 1113, 749, 700 cm–1. HR MS: calcd.
for C35H57NO14 715.3779; found 716.3868.
Bn2N-[G3.0]-OH (12): Reaction conditions and workup were as de-
scribed above, with the allyl ether 11 (100 mg, 0.096 mmol), NMO
(115 mg, 0.849 mmol, 8.8 equiv.) and K2OsO4 (1.1 mg,
0.0029 mmol, 3 mol-%) in acetone/distilled water/tert-butyl alcohol
(0.66 mL) with stirring for 16 h. Dialysis in methanol gave a brown
oil (116 mg, 0.089 mmol, 92%). 1H NMR (500 MHz, CD3OD,
25 °C): δ = 7.15–7.37 (m, 10 H), 3.51–3.76 (m, 80 H), 3.00 (m, 1
H) ppm. 13C NMR (125 MHz, CD3OD, 25 °C): δ = 142.1, 129.9,
129.6, 129.2, 127.9, 80.2 (2ϫ), 80.1, 80.0, 79.9, 74.0 (2ϫ), 73.0,
72.7, 72.5 (2ϫ), 72.4, 72.2, 72.1, 71.7, 71.3, 71.2, 64.5, 58.1,
56.2 ppm. FAB MS: calcd. for C59H105NO30 1307.6721; found
1308.04 [M + H]+.
72.3, 71.61, 71.3, 71.1, 69.8, 60.5 ppm. IR: ν = 3080, 2866, 2099,
˜
1645, 1271, 1111, 996, 924, 558 cm–1. FAB MS: calcd. for
C21H35N3O6 425.25; found 448.2 [M + Na]+, 426.3 [M + H]+.
C21H35N3O6 (425.52): calcd. C 59.27, H 8.29, N 9.88; found C
59.29, H 8.30, N 9.68.
N3-[G2.5]-allyl (19): Reaction conditions and workup were as de-
scribed above, with the alcohol 18 (1.98 g, 3.525 mmol), TBAI
(0.521 g, 1.41 mmol, 10 mol-%), NaOH (50%, 5.64 mL, 70.5 mmol,
2.5 equiv. per OH group) and allyl bromide (6.14 mL, 70.5 mmol,
2.5 equiv. per OH group). Purification was by flash chromatog-
raphy on silica gel (n-hexane/ethyl acetate, 6:1), providing title com-
pound 6 (2.0 g, 2.25 mmol, 64%) as a colorless oil. 1H NMR
(500 MHz, CDCl3, 25 °C): δ = 5.89 (tddd, J = 16.7, 10.4, 8.6,
5.6 Hz, 8 H), 5.26 (qdd, J = 17.2, 6.0, 1.6 Hz, 4 H), 5.16 (dddd, J
= 10.4, 6.4, 3.0, 1.3 Hz, 4 H), 4.12 (ddd, J = 5.6, 1.2 Hz, 4 H), 3.98
(td, J = 5.6, 1.4 Hz, 4 H), 3.70–3.51 (m, 15 H) ppm. 13C NMR
(125 MHz, CDCl3, 25 °C): δ = 135.3, 135.3, 134.9, 134.8 (4 C),
117.0, 116.9, 116.89, 116.78 (4 C), 78.6, 72.4, 71.7 (2 C), 71.4 (2
N3-[G2.0]-OH (18): A 100 mL round-bottomed flask, containing a
magnetic stirrer, was charged with tert-butyl alcohol (20 mL), water
(20 mL) and AD-mix-α or AD-mix-β (5.6 g, 1.4 g of AD-mix-α/
AD-mix-β per 1 mmol of olefin/double bond). The mixture was
stirred at room temperature until both phases were clear, and was
then cooled to 0 °C. Compound 17 (1 mmol, 0.425 g) was then
added in one portion, and the heterogeneous slurry was stirred vig-
orously at 0 °C until TLC revealed the absence of the starting olefin
(24 h). The reaction was quenched at 0 °C by addition of sodium
sulfite (1.5 g per 1 mmol of double bond), and the mixture was
then warmed to room temperature and stirred for 30–60 min. The
reaction mixture was extracted several times with an ethyl acetate/
ethanol (4:1) mixture, dried under Na2SO4 and concentrated to give
a clean product (0.3766 g, 67%). 1H NMR (500 MHz, CD3OD,
25 °C): δ = 3.78–3.74 (m, 6 H), 3.73–3.66 (m, 4 H), 3.65–3.51 (m,
21 H), 3.50–3.46 (m, 4 H) ppm. 13C NMR (125 MHz, CD3OD,
25 °C): δ = 80.0, 79.1, 74.0, 73.9, 72.4, 72.2, 71.2, 64.5, 62.6,
C), 70.5, 70.3, 60.8 ppm. IR: ν = 3079, 2867, 2099, 1646, 1270,
˜
1109, 997, 924 cm–1. FAB MS: calcd. for C45H75N3O14 881.52;
found 904.3 [M + Na]+. C45H75N3O14 (882.09): calcd. C 61.27, H
8.57, N 4.76; found C 61.16, H 8.68, N 4.73.
General Procedure for the Dihydroxylation of the Allyl Groups:
K2OsO4 (0.25–0.5 mol-% per allyl group) was added to a solution
of the allyl ether and N-methylmorpholine N-oxide (NMO,
1.1 equiv. per allyl group) in acetone/distilled water/tert-butyl
alcohol (5:5:1). The mixture was stirred at 30–40 °C for 12–24 h.
The volatile compounds were removed under vacuum, and the
product was further purified by silica gel column chromatography,
Sephadex column chromatography or dialysis.
62.3 ppm. IR: ν = 3384, 2877, 2514, 2114, 1458, 1270, 1116, 930,
˜
674 cm–1. FAB MS: calcd. for C21H43N3O14 561.27; found 583.9
[M + Na]+, 562.0 [M + H]+. C21H43N3O14 (561.58): calcd. C 44.91,
H 7.72, N 7.48; found C 44.54, H 7.72, N 7.46.
N3-[G3.0]-OH (20): Reaction conditions and workup were as de-
scribed above, with the allyl ether 19 (506 mg, 0.573 mmol), NMO
(682 mg, 4.13 mmol) and K2OsO4 (8.4 mg, 0.023 mmol, 3 mol-%),
and additionally citric acid monohydrate 0.868 g (4.13 mmol, as a
cooxidant), in distilled water/tert-butyl alcohol (1.0 mL), with stir-
ring for 24 h. Dialysis in methanol gave a light brown oil (563 mg,
Bn2N-[G1.0]-OH (8): Reaction conditions and workup were as de-
scribed above, with the allyl ether 7 (1 g, 2.845 mmol), NMO
(46 mg, 6.26 mmol, 2.2 equiv.) and K2OsO4 (10.5 mg, 0.0285 mmol,
1 mol-%) in acetone/distilled water/tert-butyl alcohol (13.2 mL). A
black viscous oil (1.44 g) was obtained as crude product, part of
which was purified by flash column chromatography (methanol/
1
85%). H NMR (500 MHz, CD3OD, 25 °C): δ = 3.78–3.74 (m, 13
H), 3.73–3.66 (m, 12 H), 3.65–3.51 (m, 42 H), 3.50–3.46 (m, 8 H)
ppm. 13C NMR (125 MHz, CD3OD, 25 °C): δ = 80.4, 80.2, 79.9,
60
www.eurjoc.org
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 53–63

Monoamino Polyglycerol Dendrons and Dendritic Triblock Amphiphiles
74.0, 73.97, 73.0, 72.4, 72.3, 72.2, 71.2, 64.5, 62.8 ppm. IR: ν =
Synthesis of Acetal-Protected Triglycerol Azide 15: Methanesulfo-
nyl chloride (5.06 mL, 65.55 mmol) was added to a solution of 14
(20.0 g, 62.43 mmol) and triethylamine (9.21 mL, 65.55 mmol) in
toluene (160 mL), cooled to 0 °C in an ice bath. Progress of the
reaction was monitored by TLC. After completion, the precipitate
was filtered and the mixture concentrated under vacuum to give an
oil as a final product (100%). The crude product was used for the
next reaction step. 1H NMR (250 MHz, CDCl3, 25 °C): δ = 4.83
(q, 1 H), 4.23 (q, 2 H), 4.01 (t, 2 H), 3.72–3.66 (m, 6 H), 3.56–3.51
(m, 4 H), 3.07 (s, 3 H), 1.39 (s, 6 H, CH3), 1.33 (s, 6 H, CH3) ppm.
13C NMR (65 MHz, CDCl3, 25 °C): δ = 109.5, 79.8, 74.5, 72.6,
72.4, 70.66, 70.64, 66.3, 38.4, 26.7, 25.3 ppm. Sodium azide
(0.157 mol, 10.2 g) was added to a solution of the mesyl triglycerol
(65.55 mmol) in dry DMF (150 mL). After the mixture had been
stirred at 120 °C under argon for 3 h, the excess of NaN3 was fil-
tered off, and DMF was removed under high vacuum by cryodis-
tillation. The crude product was purified by filtration through a
thin layer of silica gel (ethyl acetate/hexane, 2:1). The [G1.0]-N3
was obtained as a light yellow, viscous oil in 96% yield over two
steps. 1H NMR (500 MHz, [D6]acetone, 25 °C): δ = 4.21 (q, J =
11.7, 6.2, 5.6 Hz, 2 H), 4.03 (ddd, J = 8.2, 6.4, 1.0 Hz, 2 H), 3.76
(m, 1 H), 3.72 (dd, J = 8.2, 6.3 Hz, 2 H), 3.67 (tdd, J = 9.6, 7.8,
4.5 Hz, 2 H), 3.61 (ddd, J = 5.5, 5.0, 2.2 Hz, 2 H), 3.54 (ddd, J =
17.9, 10.3, 5.1 Hz, 4 H), 1.34 (s, 6 H) 1.28 (s, 6 H) ppm. 13C NMR
(125 MHz, [D6]acetone, 25 °C): δ = 109.6, 75.51, 75.50, 73.0, 72.9,
˜
3382, 2877, 2514, 2113, 1463, 1330, 1124, 930, 677 cm–1. ESI TOF
MS: calcd. for C45H91N3O30 1153.5687; found 1176.5615
[M + Na]+.
General Procedure for the Deprotection of the Amino Functionality:
Pd/C (10–25 wt.-%) was added to a methanol solution of the po-
lyol, either with benzyl protection or with an azide group, and the
mixture was stirred under hydrogen pressure for 24–48 h. The cata-
lyst was filtered through Celite® pads and washed with methanol.
The organic layer was concentrated in vacuo, yielding a clean prod-
uct.
H2N-[G1.0]-OH (21): Reaction conditions and workup were as de-
scribed above, with 8 (2.01 g, 4.79 mmol) and Pd/C (500 mg) and
stirring at a pressure of 5 bar of H2 for 18 h. Amine 21 was isolated
1
as a light yellow oil (1.143 g, 99%). H NMR (500 MHz, CD3OD,
25 °C): δ = 3.85–3.81 (m, 2 H), 3.63–3.38 (m, 12 H), 3.33–3.13 (m,
1 H) ppm. 13C NMR (125 MHz, CD3OD, 25 °C): δ = 73.8 (2ϫ),
73.7 (2ϫ), 72.2 (2ϫ), 64.3, 51.9 ppm. IR: ν = 3343, 2924, 2287,
˜
1662, 1601, 1456, 1113, 1049 cm–1. HR FAB MS: calcd. for
C9H21NO6 239.1369; found 240.1475 [M + H]+.
H2N-[G2.0]-OH (22): Reaction conditions and workup were as de-
scribed above, with 10 (167 mg, 0.23 mmol) and Pd/C (41 mg) and
stirring at a pressure of 5 bar of H2 for 18 h. Amine 22 was isolated
as a light yellow oil (0.218 mg, 95%). 1H NMR (500 MHz,
CD3OD, 25 °C): δ = 3.74 (m, 4 H), 3.66 (m, 4 H), 3.60–3.38 (br. m,
26 H), 3.06 (m, 1 H) ppm. 13C NMR (125 MHz, CD3OD, 25 °C): δ
71.7, 71.6, 67.2, 61.5, 27.1, 25.7 ppm. IR: ν = 2987, 2935, 2875,
˜
2100, 1456, 1380, 1371, 1258, 1214, 1081, 1055, 975, 844, 515 cm–1.
FAB MS (MNBA): calcd. for C15H27N3O6 345.39; found 368.2 [M
+ Na]+, 346.3 [M + H]+. C15H27N3O6 (345.39): calcd. C 52.16, H
7.88, N 12.17; found C 52.03, H 7.46, N 11.84.
= 79.8, 74.0, 73.2, 72.9, 72.4, 72.2, 64.4, 51.9 ppm. IR: ν = 3398,
˜
2931, 2881, 1660, 1464, 1363, 1113, 935, 870 cm–1. ESI TOF MS:
calcd. for C21H45NO14 535.2840; found 558.2718 [M + Na]+,
536.2901 [M + H]+.
Synthesis of Triglycerol Azide N3-[G1.0]-OH (16): Ion-exchange
resin Dowex® 50W was added to the acetal-protected triglycerol
azide (19.3 g, 55.88 mmol), dissolved in MeOH (100 mL), and the
mixture was heated at reflux overnight. After it had cooled down,
the resin was filtered off, and the residue was concentrated under
H2N-[G3.0]-OH (23): Reaction conditions and workup were as de-
scribed above, with 12 (650 mg, 0.497 mmol) and Pd/C (163 mg)
and stirring at a pressure of 5 bar of H2 for 18 h. Amine 23 was
1
isolated as a light yellow oil (475 mg, 85%). H NMR (500 MHz,
CD3OD, 25 °C): δ = 3.73–3.44 (m, 75 H), 3.27 (m, 1 H) ppm. 13C
NMR (125 MHz, CD3OD, 25 °C): δ = 79.8; 74.0 (2ϫ), 72.9, 72.5,
1
vacuum to yield compound 16 (14.81 g, 99%) as a yellow oil. H
NMR (500 MHz, CD3OD, 25 °C): δ = 3.78–3.74 (m, 2 H), 3.68–
3.46 (m, 12 H), 3.39 (ddd, J = 13.0, 9.8, 3.7 Hz, 1 H) ppm. 13C
NMR (125 MHz, CD3OD, 25 °C): δ = 73.84, 73.80, 72.24, 72.20,
72.4 (2ϫ), 72.3 (2ϫ), 72.2, 64.4, 49.9 ppm. IR: ν = 3390, 2922,
˜
2885, 1651, 1464, 1350, 1128, 933 cm–1. ESI TOF MS: calcd. for
C45H93NO30 1127.5782; found 1150.5680 [M + Na]+, 1128.5857 [M
+ H]+.
72.12, 72.11, 64.4, 62.1 ppm. IR: ν = 3384, 2876, 2514, 2103, 1457,
˜
1273, 1127, 1047, 929, 665, 558 cm–1. ESI TOF MS: calcd. for
C9H19N3O6 265.1274; found 288.1176 [M + Na]+, 304.0824 [M +
K]+.
Acetal Protection of Triglycerol (13) To Give 14: Triglycerol (13)
(60 g, 0.25 mol) was gently heated with a heat-gun (max. 120 °C)
up to the moment at which the substance obtained a liquid consist-
ency. 2,2-Dimethoxypropane (150 mL, 1.25 mol) was added, fol-
lowed by slow addition of p-toluenesulfonic acid (PTSA, 3.0 g,
25 mmol). After stirring for 0.5 h, a homogeneous solution was ob-
tained, and the reaction was allowed to proceed at 30–40 °C over-
night. The resulting yellow/orange solution was neutralized by ad-
dition of triethylamine (25 mmol) and subsequently stirred at room
temperature for 30 min. The solvent was then evaporated in vacuo,
and the remaining crude liquid was purified by filtration through
silica gel (ethyl acetate/hexane, 1:2, 2:1, 6:1) to give the compound
(78%) as a pale yellow oil. (Triglycerol contains ca. 20% other
oligomers). 1H NMR (500 MHz, [D6]acetone): δ = 4.19 (q, J =
11.9, 6.3 Hz, 2 H), 4.00 (dd, J = 8.2, 6.4 Hz, 2 H), 3.84 (m, 1 H),
3.75 (td, J = 4.9, 1.5 Hz, 1 H), 3.69 (dd, J = 8.2, 6.3 Hz, 2 H), 3.50
(ddd, J = 31.8, 10.1, 5.5 Hz, ddd, J = 17.4, 11.9, 6.3 Hz, 8 H), 2.83
(s, 1 H, OH), 1.33 (s, 6 H, CH3), 1.28 (s, 6 H, CH3) ppm. 13C NMR
(125 MHz, [D6]acetone, 25 °C): δ = 109.4, 75.6, 73.9, 73.8, 73.14,
73.12, 70.17, 67.4, 27.1, 25.7 ppm. FAB MS (MNBA): calcd. for
General Procedure for the Coupling of the Amino Dendrons to the
Biphenyl Core: Diisopropylamine was added at 0 °C to a mixture
of biphenyl-4,4Ј-dicarboxylic acid, dicyclohexylcarbodiimide
(DCC) and hydroxybenzotriazole (HOBt) or N-hydroxysuc-
cinimide (NHS) in dry DMF (2 mL). After 5 min of stirring, the
amine in dry DMF (1 mL) was added. The reaction mixture was
warmed to room temperature and stirred for 1–3 d. The mixture
was extracted with diethyl ether and water. The aqueous layer was
extracted with diethyl ether (4ϫ). The combined organic layers
were concentrated in vacuo. The crude products were purified by
HPLC (reversed-phase column, water/methanol, 1:1; flow
9.0 mLmin–1).
Coupling of Biphenyl-4,4Ј-dicarboxylic Acid with H2N-[G1.0]-OH
To Give 25: Reaction conditions and workup were as described
above, with the biphenyl-4,4Ј-dicarboxylic acid (50 mg, 0.21 mmol),
21 (100 mg, 1.25 mmol), diisopropylamine (162 mg, 1.25 mmol),
DCC (129 mg, 0.63 mmol) and HOBt (85 mg, 0.63 mmol) in dry
C15H28O7 320.18; found 343.2 [M + Na]+, 321.3 [M + H]+. DMF (3 mL). The product was purified by RP-HPLC to yield a
C15H28O7 (320.38): calcd. C 56.23, H 8.8; found C 55.88, H 8.65.
yellow oil (46 mg, 0.07 mmol, 33%). 1H NMR (500 MHz, CD3OD,
Eur. J. Org. Chem. 2008, 53–63
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
61

B. Plietker, R. Haag et al.
FULL PAPER
[3]
[4]
a) D. A. Tomalia, H. Baker, J. Dewald, M. Hall, G. Kallos, S.
Martin, J. Roeck, J. Ryder, P. Smith, Polym. J. 1985, 17, 117–
132; b) C. J. Hawker, J. M. J. Fréchet, J. Chem. Soc. Chem.
Commun. 1990, 1010–1013; c) C. J. Hawker, J. M. J. Fréchet, J.
Am. Chem. Soc. 1990, 112, 7638–7647.
25 °C): δ = 7.93–7.90 (m, 4 H, Aryl-H), 7.75–7.73 (m, 4 H, Aryl-
H), 4.45–4.41 (m, 2 H, 1-H), 3.78–3.48 (m, 28 H, aliphatic H) ppm.
13C NMR (125 MHz, CD3OD, 25 °C): δ = 169.8, 144.2, 135.0,
131.2, 129.1, 128.1, 73.8, 73.6, 72.2, 72.1, 71.3, 71.2, 64.4,
51.0 ppm. MALDI TOF MS: calcd. for C32H48N2O14 684.31;
found 685.3 [M + H]+.
a) E. R. Gillies, J. M. J. Frechét, Drug Disc. Today 2005, 10,
35–43; b) C. C. Lee, J. A. MacKay, J. M. J. Frécht1, F. C.
Szoka, Nat. Biotechnol. 2005, 23, 1517–1526; c) K. E. Uhrich,
S. M. Cannizzaro, R. S. Langer, K. M. Shakesheff, Chem. Rev.
1999, 99, 3181–3198; d) U. Boas, P. M. H. Heegaard, Chem.
Soc. Rev. 2004, 33, 43–63; e) R. Haag, Angew. Chem. 2004, 116,
280–284; Angew. Chem. Int. Ed. 2004, 43, 278–282.
a) E. Chiellini, J. Sunamoto, C, Migliaresi, R. Ottenbrite, D.
Cohn, Biomedical Polymers and Polymer Therapeutics, Kluwer
Academic Publishers, New York, 2002; b) R. Haag, F. Kratz,
Angew. Chem. Int. Ed. 2006, 45, 1198–1215; Angew. Chem.
2006, 118, 1218–1237; c) C. C. Lee, J. A. MacKay, J. M. J.
Fréchet, F. C. Szoka, Nat. Biotechnol. 2005, 23, 1517–1526; d)
R. Satchi-Fainaro, R. Duncan, C. M. Barnes, Adv. Polym. Sci.
2006, 193, 1–65; e) T. M. Allen, P. R. Cullis, Science 2004, 303,
1818–1822.
Coupling of Biphenyl-4,4Ј-dicarboxylic Acid with H2N-[G2.0]-OH
To Give 26: Reaction conditions and workup were as described
above, with the biphenyl-4,4Ј-dicarboxylic acid (23 mg, 0.09 mmol),
22 (100 mg, 0.186 mmol), diisopropylamine (72 mg, 0.56 mmol),
DCC (58 mg, 0.28 mmol) and HOBt (38 mg, 0.28 mmol) in dry
DMF (3 mL). The product was purified by dialysis (cutoff 500,
24 h, methanol), and RP-HPLC yielded a yellow oil (35 mg,
[5]
1
0.027 mmol, 29%). H NMR (500 MHz, CD3OD, 25 °C): δ = 7.96
(d, J = 8.4 Hz, 4 H, Aryl-H), 7.80 (d, J = 8.4 Hz, 4 H, Aryl-H),
4.47–4.44 (m, 2 H), 3.75–3.44 (m, 70 H, aliphatic H) ppm. 13C
NMR (125 MHz, CD3OD, 25 °C): δ = 169.8, 144.4, 135.0, 129.2,
128.2, 79.8, 73.9, 72.9, 72.4 (2ϫ), 72.3, 72.1 (2ϫ), 71.4, 64.3,
51.0 ppm. HR MS:calcd. for C56H96N2O30 1276.6048; found
1299.5931 [M + Na]+.
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Coupling of Biphenyl-4,4Ј-dicarboxylic Acid with H2N-[G3.0]-OH
To Give 27: Reaction conditions and workup were as described
above, with the biphenyl-4,4Ј-dicarboxylic acid (21.5 mg,
0.09 mmol), 23 (200 mg, 0.177 mmol), diisopropylamine (69 mg,
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[8]
[9]
1
(53 mg, 0.02 mmol, 24%). H NMR (500 MHz, CD3OD, 25 °C): δ
[10]
= 8.11–7.94 (m, 4 H, Aryl-H), 7.87–7.77 (m, 4 H, Aryl-H), 4.52–
4.48 (m, 2 H), 3.78–3.44 (m, 150 H, aliphatic H) ppm. 13C NMR
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64.2, 51.0 ppm. MADLI TOF MS: calcd. for C104H192N2O62
2461.1933; found 2483.66 [M + Na]+, 2461.22 [M + H]+.
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The IUPAC names of the compounds described in this paper
are complicated and too long, and the designed structure can-
not easily or quickly be concluded. Therefore, we have applied
Encapsulation Procedure: The dendritic triblock amphiphiles were
dissolved in 5 mL of water at concentrations of 1.0, 5.0 and
10.0 gL–1, Nile Red (5 mg) was added as a fine powder, and the
mixtures were stirred for 24 h. Insoluble solid residues of dye were
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[13]
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Acknowledgments
This work was supported by the Studienstiftung des deutschen
Volkes (grant for K. M.), the Fonds der Chemischen Industrie (Lie-
big fellowship for B. P.) and the Deutsche Forschungsgemeinschaft
(Emmy-Noether fellowship for B. P.). R. H. is indebted to the Bun-
desministerium für Forschung und Bildung (BMBF) for a young
scientist nanotechnology award. M. W. and R. H. thank Dr. W.
Dilla from Solvay Chemicals GmbH for a generous gift of high-
purity triglycerol. The authors thank M. Radowski for helpful dis-
cussions.
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www.eurjoc.org
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 53–63

Monoamino Polyglycerol Dendrons and Dendritic Triblock Amphiphiles
a simple name system for our bifunctional dendrons. The name
of each compound consist of three parts: H2N-[G1.0]-OH,
whereby H2N- is the core, [G1.0] is the number of the genera-
tion, and -OH is the shell.
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(reaction temperature and co-oxidants like NMO/citric acid or
citric acid/H2O2) without success.
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Received: July 24, 2007
Published Online: November 15, 2007
Eur. J. Org. Chem. 2008, 53–63
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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