Synthesis and characterization of a novel biodegradable amphiphilic dendritic polyether-ester

Article abstract of DOI:10.1071/CH12013

A novel biodegradable amphiphilic dendritic polyether-ester composed of glycerol, glycolic acid oligomer and methoxy poly(ethylene glycol) is described. The monomer unit composed of glycerol and glycolic acid was protected by tert-butyl and benzyl groups.

Full text of DOI:10.1071/CH12013

CSIRO PUBLISHING
Aust. J. Chem. 2012, 65, 545–551
Full Paper
http://dx.doi.org/10.1071/CH12013
Synthesis and Characterization of a Novel Biodegradable
Amphiphilic Dendritic Polyether-ester
A
A
A
A
Jin peng Xiao, Hong Wang, Qiang Yi, Gejun Ma,
A B C
, ,
and Xue fei Zhang
A
College of Chemistry, Xiangtan University, Xiangtan, 411105, Hunan Province, China.
Key Laboratory of Environmentally Friendly Chemistry and Applications of Ministry
of Education, College of Chemistry, Xiangtan University, Xiangtan, 411105, China.
B
C
Corresponding author. Email: zxf7515@yahoo.com.cn
A novel biodegradable amphiphilic dendritic polyether-ester composed of glycerol, glycolic acid oligomer and methoxy
poly(ethylene glycol) is described. The monomer unit composed of glycerol and glycolic acid was protected by tert-butyl
and benzyl groups. The amphiphilic dendritic polyether-ester was prepared in high yield using sequential deprotection
reactions and esterification. The structure of all compounds was confirmed by 1H NMR spectra, 13C NMR spectra, GC-MS
or matrix-assisted laser desorption–ionization time-of-flight mass spectrometry, and the amphiphilic dendritic macro-
molecule molecular weight and distribution were measured by gel permeation chromatography.
Manuscript received: 14 January 2012.
Manuscript accepted: 17 February 2012.
Published online: 14 May 2012.
Introduction
macromolecules. Linear dendritic block copolymers are usually
composed of poly(ethylene glycol) and a hydrophobic dendritic
block.[15] Furthermore, the size of dendrimers formed by these
polymers tends to be uniform.[16] Some poorly water-soluble
drugs and fluorescent probes have been physically encapsulated
into these micelles.[2,15,16] Although many linear dendritic block
copolymers have been explored, identification of new mono-
mers and synthesis of novel biodegradable linear dendritic block
copolymers remain an active area of research.
Dendrimers are monodisperse synthetic macromolecules built
from branched repeating units around a core. Dendrimers are
synthesized stepwise, resulting in precisely controlled size and
structure, and a well-defined number of surface end-groups.[1]
Thus, dendrimers provide opportunities to fine-tune their com-
position and structure to afford macromolecules with specific
properties for basic studies and applications in areas such as
molecular encapsulation,[2] catalysis,[3] light-harvesting,[4] gene
transfection[5] and drug delivery.[6] For example, poly-
amidoamine, polyethyleneimine and poly(propyleneimine) are
some of the most widely used dendrimers in gene and drug
delivery application[7–9] for increasing water solubility, bio-
compatibility and so on. However, these dendrimers also have
some inherent drawbacks for biological use. Their polycationic
surfaces lead to significant toxicity[7,9]; furthermore, these are
all non-biodegradable.[9]
In recent years, much effort devoted to the preparation of
dendrimers has explored polyesters as promising candidates for
biological applications.[7,9] Owing to their intrinsic properties
such as non-immunogenicity, good biocompatibility and biode-
gradability, they could be widely used in biomedical applica-
tions,[7,9–11] including sutures, scaffolds in tissue engineering
and carriers in drug delivery. Several polyester dendrimers such
as PMPA dendrimers[12] (based on 2,2-bis(hydroxymethyl)
propanoic acid), PGLSA dendrimers[13] (based on glycerol
and succinic acid) have been reported, and have demonstrated
potential use in biological applications.[14]
In 2001, the Grinstaff group first reported a novel polyester
dendrimer that was synthesized using the divergent method with
glycerol and lactic acid as the growth unit (PGLLA dendri-
mers),[17] and reported that PGLLA dendrimers degrade faster
than PGLSA dendrimers.[10] They attribute this reactivity dif-
ference to the hydrophobicity and the inherent chemical reac-
tivity present in the macromolecule (facile loss of monomer unit
by an internal six-member cyclization reaction). The excellent
degradation properties of polyether-ester dendrimers could help
in achieving a desired degradation rate for specific in vivo
applications. Despite these appealing advantages, no further
study has been reported so far, mainly due to the difficult
monomer synthesis and limited available synthetic methods
(divergent method only).[17] The use of glycerol and glycolic
acid to synthesize hyperbranched polymers has been reported
recently.[18] However, that AB2 monomer units synthesis was
very difficult and tedious, and they were not suitable as
dendrimer monomer units. Herein, we report a facile synthetic
method of branching AB2 monomer units composed of glycerol
and glycolic acid. Two facile ways were used to introduce
glycolic acid into this AB2 monomer, and every glycolic acid
could be replaced by other analogues,[19,20] such as lactic acid,
glycolic acid oligomer and lactic acid oligomer. Those strategies
Among the various dendritic macromolecules studied, linear
dendritic block copolymers have emerged as an interesting class
of dendrimer derivatives because of the interesting assemblies
they can form in solution, on surfaces, or in the presence of other
Journal compilation Ó CSIRO 2012
www.publish.csiro.au/journals/ajc

546
J. Xiao et al.
O
O
O
Br
O
O
O
O
O
(b)
OH
O
(a)
O
O
O
O
O
O
OH
HO
HO
O
O
O
O
O
O
(c)
O
O
Pro-G1
(d)
O
O
O
O
O
O
O
O
(e)
O
O
HO
O
O
O
O
O
O
O
O
O
G1
Pro-G1COOH
Scheme 1. Synthesis of AB2 monomer unit (dendron G1): (a) tert-butyl bromoacetate, KOH, PEG6000, K2CO3, room temp;
(b) p-toluenesulfonic acid, ethanol, H2O, 508C; (c) DCC, DMAP, DCM, 08C; (d) TFA, DCM, triethylsilane, 08C; (e) tert-butyl
bromoacetate, TBAB, acetone, 708C.
would greatly increase the variability of dendrons, dendrimers
and their derivatives, providing new opportunities to create
tailored polymers that could regulate the degradation rate and
other chemical and physical properties. Moreover, we used that
AB2 monomer unit and glycolic acid oligomer to synthesize a
series of polyether-ester dendrons by the convergent method.
Further, we used methoxy poly(ethylene glycol) (MPEG) con-
junct dendrons as building block polymers. In addition, the
MPEG-block-dendritic copolymer used benzyl protecting
groups, which can be selectively removed in very high yields
by catalytic hydrogenolysis without affecting the ester bonds of
the polyester backbone, and the hydroxyl-terminated block
polymer can be used in drug delivery[14] or photo-crosslinked
dendritic gels.[13] These properties are likely to facilitate the
design and development of new materials and provide new
opportunities to create well-defined, tailored polymers for
specific medical and tissue-engineering applications.
dicyclohexylcarbodiimide(DCC) chemistry. Thetert-butyl of the
protected dendron pro-Generation 1 (pro-G1) was deprotected by
CF3COOH and yielded the carboxylic acid-terminated dendron
pro-G1COOH. The pro-G1COOH reacted with tert-butyl bro-
moacetate by KBr exchange with K2CO3 as base and produced a
novel bi-protected AB2 monomer unit (dendron Generation 1)
protected by tert-butyl and benzyl groups. As mentioned above,
the benzyl and tert-butyl groups can be selectively removed by
using hydrogen with a palladium catalyst and CF3COOH
respectively.
The strategy for the synthesis of dendrons Generation 1 (G1)
to Generation 3 (G3) is outlined in Scheme 2. The protected G1
was deprotected by CF3COOH to yield the carboxylic acid-
terminated dendron G1COOH. The benzyl group of G1 was
subsequently removed by hydrogenolysis (10 % (w/w) of 10 %
Pd/C, 2.9 MPa H2, in CH3OH) to produce a hydroxyl-terminated
G1OH. Next, dendrons G1OH and G1COOH were coupled in
the presence of DCC and dimethylaminopyridine (DMAP) to
afford the protected G2 dendron; the G2 dendron was depro-
tected in CF3COOH/CH2Cl2 (1 : 1) to yield the carboxylic acid-
terminated dendron G2COOH. The dendron G3 was prepared
by reacting dendron G1OH with G2COOH. The tert-butyls of
dendron G3 were subsequently removed by CF3COOH to yield
the carboxylic acid-terminated dendron G3COOH. All reactions
were conducted under mild conditions and had excellent yields.
The esterification and deprotection reactions were monitored by
NMR spectroscopy as the relative integrated areas of the
aromatic, glycerol and tert-butyl protons change with each
successive generation. The phenyl, methylene and tert-butyl
groups could serve as diagnostic NMR tags to monitor the
Results and Discussion
The strategy for the preparation of the monomer unit is outlined
in Scheme 1. Transformation of 5-phenyl-1,4-dioxan-2-ol into
tert-butyl-2-(1,3-dihydroxypropan-2-yloxy)acetate was easily
carried out in a yield of 80% by KBr exchange under mild con-
ditions. In this reaction, KOH was used as base rather than Na or
NaH, which need anhydrous, anaerobic and low-temperature
conditions. The benzylidene acetal group of the tert-butyl-2-(1,3-
dihydroxypropan-2-yloxy)acetate was subsequently removed by
hydrogenolysis (with p-toluenesulfonic acid as a catalyst) to yield
the 2-(1,3-dihydroxypropan-2-yloxy)acetate. The hydroxyl
groups were then protected with benzyloxyacetic acid using

Amphiphilic Dendritic Polyether-ester
547
OH
OH
O
O
(a)
G1
(b)
O
O
O
O
O
O
O
G1OH
G2
OR
OR
(b)
G1OH
(c)
O
O
O
G2COOH
HO
O
(c) G1OH
G3
G1COOH
OR
OR
(b)
O
O
O
O
OR
OR
O
O
O
O
3
O
O
O
O
O
O
O
HO
O
O
O
3
O
O
OR
OR
G3COOH
O
O
(c)
MPEG5000
OR
OR
G3
MPEG5000
O
C
CH2OCH2
Rϭ
Scheme 2. Synthesis of dendron G1 to MPEG-(polyether-ester) dendritic (a) Pd/C, H2, CH3OH, room temp;
(b) TFA, DCM, triethylsilane, room temp; (c) DCC, DMAP, CH2Cl2, 08C.
The 1H NMR spectra of dendrons G1 to G3 are compared in
Fig. 1. Peaks at 7.35 ppm were attributed to the phenyl protons
(Ha) of the benzyl group; the single peak at 1.47 ppm belongs to
Ha
Ha
Hc
1
the tert-butyl (Hc) group. The H NMR spectra of dendrons
Hb
G1COOH to G3COOH are shown in Fig. 2. The disappearance
of peaks at 1.47 ppm indicates the complete removal of the tert-
butyl group. In addition, the dendrons’ purity and molecular
weight could be determined by MALDI-TOF (matrix-assisted
laser desorption–ionization time-of-flight) mass spectrometry.
The MALDI-TOF spectra of protected dendrons is shown in
Fig. 3. In all cases, a strong signal for the molecular ion is
observed at the expected molecular weight (G1 599.3 (M þ K),
G2 1391.3 (M þ K) and G3 2976.0 (M þ K)) and there is no sign
of incomplete branches. A abnormal feature was observed in the
spectra of every dendron, which showed the presence of strong
peaks of lower mass by ,56 from the mass ions corresponding
to the desired products, ascribed to the tert-butyl group of the
dendrons being easily lost in laser excitation.[21] The MALDI-
TOF MS spectra of deprotected dendrons are shown in Fig. 4. In
this case, two strong peaks (M þ 39, M þ 77) were observed in
the spectra, which correspond to the Kþ adduct and 2Kþ adduct
(the hydrogen ion of the carboxyl was replaced by a K ion).
The strategy for the synthesis of dendritic MPEG-(polyether-
ester) is outlined in Scheme 2. MPEG5000 and dendron
G3COOH were coupled in the presence of DCC and DMAP
to afford the MPEG-(polyether-ester) dendritic copolymer.
Hc
Hc
Hb
Ha
Hb
8
7
6
5
4
3
2
1
Chemical shift [ppm]
Fig. 1. 1H NMR spectrum of G1 to G3 dendrons.
increase of dendron generation, as they are recognizable in every
dendron molecule from G1 to G3, and we could use the inte-
gration ratio (phenyl/methylene/tert-butyl ¼ 10 : 1 : 9, 20 : 3 : 9,
40 : 7 : 9 for G1, G2 and G3 respectively) to judge whether the
generation increase was successful or not.

548
J. Xiao et al.
2920
1335
Ha
Ha
Hb
Hb
543
581
2958
1373
Ha
Hb
500
1000
1500
2000
2500
3000
8
7
6
5
4
3
2
1
Mass [m/z]
Chemical shift [ppm]
Fig. 4. MALDI-TOF (matrix-assisted laser desorption–ionization time-of-
Fig. 2. 1H NMR spectrum of G1COOH to G3COOH dendrons.
flight) mass spectra of G1COOH to G3COOH deprotected dendrons.
1000
800
600
400
200
0
(a)
2500
7791
7759
2921
2979
2000
1500
1000
500
0
7967
1391
7256
8100
599
1335
543
4000
5000
6000
7000
8000
9000
Mass [m/z]
3000
2000
1000
7791
Mass [m/z]
800
600
400
200
0
7835
(b)
7703
7747
7659
7615
7879
Fig. 3. MALDI-TOF (matrix-assisted laser desorption–ionization time-of-
flight) mass spectra of G1 to G3 dendrons.
The molecular weights of the dendrons and the linear-
MALDI-TOF mass spectrum are summarized in Fig. 5. The
spectrum now consists of a series of peaks centred at a mass of
7791, exhibits the expected mass difference of 44 between
individual components, and shows no signs of unreacted
MPEG5000. The linear dendritic copolymer gel permeation
chromatography (GPC) curves (polystyrene standard and
DMF as eluent) show a unimodal peak (Fig. 6); compared with
MPEG5000 and G3COOH, it can be seen that the molecular
weight distribution of the copolymers was controlled to a very
narrow range. The molecular weight and molecular weight
distribution are 16819 and 1.04 respectively. These data all
imply that the dendritic copolymers were obtained successfully.
7600
7700
7800
7900
Mass [m/z]
Fig. 5. MALDI-TOF (matrix-assisted laser desorption–ionization time-of-
flight) mass spectra of dendritic.
Conclusion
The synthesis and characterization of glycerol and glycolic acid
oligomer dendrons as well as linear dendritic copolymers
composed of glycerol, glycolic acid oligomer and methoxy poly
(ethylene glycol) are described. This synthesis yields a novel
AB2 monomer unit protected by tert-butyl and benzyl groups.
Dendrons were prepared in high yield using sequential
deprotection reactions and esterification. The oligomers were
introduced successfully into the dendritic polymers and could
increase its variability and keep biocompatibility and biode-
gradability. This biocompatible, biodegradable amphiphilic
dendritic polyether-ester expands the repertoire of polymers
available for study, and is believed to have potential applications

Amphiphilic Dendritic Polyether-ester
549
MPEG-G3
G3COOH
(0.5 g) and an additional of 5 mL distilled water were added. The
reaction mixture was stirred for 30 min at 508C. The reaction
progress was monitored by TLC. After reaction, the mixture was
evaporated and dissolved into dichloromethane (20 mL). The
solution was washed with saturated aqueous sodium bicarbon-
ate, and dried with MgSO4, and then evaporated. Yield 2.90 g
(86 %) of tert-butyl-2-(1,3-dihydroxypropan-2-yloxy)acetate as
a colourless liquid. dH (400 MHz, CDCl3) 1.49 (9H, C(CH3)3),
3.51–3.54 (1H, CH), 3.70–3.71 (4H, CH2–CH), 4.17 (CH2CO).
dC (100 MHz, CDCl3) 171.6, 83.5, 82.7, 68.1, 62.4, 28.0.
m/z (GC-MS) Calc. for C9H18O5: 206. Found: 207 (M þ H).
MPEG
Synthesis of Dendron Pro-G1
10
15
In a flask equipped with a magnetic stirrer, tert-butyl-2-
(1,3-dihydroxypropan-2-yloxy)acetate (4g, 20.0mmol) and
benzyloxyacetic acid (6.64 g, 40.04 mmol) were dissolved in
dichloromethane (100mL), and then DMAP (catalytic amount)
and DCC (4.13 g, 40.04 mmol) were added. Stirring at 08C was
continued for 14 h. The DCC-urea was filtered and washed with a
small amount of dichloromethane (10 mL), and the filtrate was
evaporated. The crude product was purified by silica gel chroma-
tography (ethylacetate/hexane1 : 5)toyield4.65g ofa colourless
liquid (95 % yield). dH (400 MHz, CDCl3) 7.30–7.37 (10H,
C6H5), 4.63 (4H, CH2C6H5), 4.24–4.38 (4H, CH2CH), 4.08–
4.19 (4H, CH2CO), 3.87–3.90 (1H, CH), 1.45 (9H, C(CH3)3). dC
(100MHz, CDCl3) 170.0, 169.0, 137.1, 128.4, 128.2, 128.1,
128.0, 127.8, 81.9, 75.5, 73.4, 67.9, 67.0, 63.2, 28.0. m/z
(MALDI-TOF) Calc. for C27H34O9: 502. Found: 541 (Mþ K)þ.
Fig. 6. Gel permeation chromatography curves of dendritic copolymers.
in controlled drug release in the biomedical and tissue engi-
neering field.
Experimental
General Procedures and Requirements
1H NMR spectra were recorded on a Bruker AV-400 M in
CDCl3. Chemical shifts are given in parts per million with
respect to tetramethylsilane as an internal reference. 13C NMR
spectra were recorded on a Bruker AV-400 M in CDCl3; GPC
measurements were conducted with a PL-GPC120 (DMF as
eluent, polystyrene standard). Mass spectrometry measurements
were carried out using GC-MS (Agilent 7890–5975C GC-MSD,
ethyl acetate as solvent) or MALDI-TOF (BrukerSaxonia
Reflex IV apparatus equipped with a 337-nm nitrogen laser, 2,5-
dihydroxy benzoic acid and 2-hydroxy-5-methoxybenzoic acid
(9 : 1 w/w) as the matrix and CF3COOK as cationic reagent).
Synthesis of Dendron Pro-G1COOH
In a flask equipped with a magnetic stirrer, dendron pro-G1
(10 g, 22.42 mmol) was dissolved in anhydrous CH2Cl2
(30 mL). The solution was chilled to room temperature and
treated with trifluoroacetic acid (TFA, 15 mL) and triethylsilane
(1 mL). After stirring for 2 h, TFA and CH2Cl2 were removed
under reduced pressure. The residue was dissolved in saturated
aqueous sodium bicarbonate, and extracted with dichloro-
methane twice. Removing the organic extract, the aqueous layer
(adjusted to pH 3.0 with 1 M HCl) was extracted with dichlor-
omethane three times and the extracts were dried over MgSO4.
The product was obtained by removal of the solvent from the
dried extract. dH (400 MHz, CDCl3) 7.30–7.37 (10H, C6H5),
4.63 (4H, CH2C6H5), 4.13–4.40 (6H, CH2CHCH2CO), 4.06
(4H, CH2CO), 3.88–3.90 (1H, CH). dC (100 MHz, CDCl3)
173.1, 170.0, 136.9, 128.5, 128.3, 128.1, 128.0, 76.3, 73.4,
67.2, 67.0, 63.2. m/z (MALDI-TOF) Calc. for C23H26O9: 446.
Found: 485 (M þ K)þ, 523 (M þ Kþ þ Kþ ꢀ H).
Synthetic Procedures and Physical Data
for All New Compounds
Benzyloxyacetic acid and 5-phenyl-1,4-dioxan-2-ol were syn-
thesized according to literature procedures.[19,22]
Synthesis of tert-Butyl-2-(2-phenyl-1,3-dioxan-5-yloxy)
acetate
To a one-necked flask equipped with a magnetic stirrer was
added 5-phenyl-1,4-di-oxan-2-ol (10.0 g, 55.5 mmol), followed
by dichloromethane (100 mL), 5.1 g (90 mmol) KOH and a
catalytic amount of poly(ethylene glycol) (Mn = 2000). The
mixture was stirred for 24 h at room temperature. Reaction
progress was monitored by TLC. After the disappearance of
the 5-phenyl-1,4-dioxan-2-ol, the reaction mixture was filtered,
and the filtrate was evaporated to dryness. The product was
purified by recrystallization in cold (ꢀ218C) hexane to get a
white solid (90 % yield). dH (400 MHz, CDCl3) 7.35–7.53 (5H,
C6H5), 5.57 (1H, C6H5CH), 4.1–4.44 (6H, CH2CHCH2CO), 3.54
(1H, CH2CH), 1.49 (9H, C(CH3)3). dC (100 MHz, CDCl3) 28.1,
66.3, 69.0, 70.6, 81.6, 101.2, 126.1, 128.1, 128.8, 138.1, 169.8.
m/z (GC-MS) Calc. for C16H22O5: 294. Found: 293 (M ꢀ H).
Synthesis of Dendron G1
In a flask equipped with a magnetic stirrer, glycolic acid
(4.46 g, 0.010 mol) was dissolved in 150 mL of acetone and
KHCO3 (15.2 g, 0.152 mol) was added. The mixture was stirred
for ,2 h. tert-Butyl bromoacetate (2.14 g, 0.011 mol) and tetra-
butylammonium bromide (cat.) were added. The reaction mix-
ture was stirred for 48 h at 708C and then filtered; the solvent was
removed under reduced pressure. Column chromatography
(silica gel, ethyl acetate/hexane) yielded 5.21 g (93 %) of den-
dron G1. dH (400 MHz, CDCl3) 7.30–7.37 (10H, C6H5), 4.63
(4H, CH2C6H5), 4.53 (2H, COCH2CO) 4.24–4.39 (6H,
CH2CHOCH2CO), 4.08–4.14 (4H, C6H5CH2OCH2), 3.92–
3.95 (1H, CH), 1.49 (9H, C(CH3)3). dC (100 MHz, CDCl3)
170.0, 169.3, 166.2 137.0, 128.5, 128.3, 128.02, 128.0, 82.7,
Synthesis of tert-Butyl-2-(1,3-dihydroxypropan-2-yloxy)
acetate
Compound 6 (5 g, 18.52 mmol) was added to a one-necked
flask equipped with a magnetic stirrer, followed by 30 mL of
ethanol. When the solid had dissolved, p-toluenesulfonic acid

550
J. Xiao et al.
75.9, 73.4, 67.2, 67.0, 66.9, 63.2, 61.3, 28.0. m/z (MALDI-TOF)
Calc. for C29H36O11: 560. Found: 599 (M þ K)þ.
(20H, C6H5), 4.65–4.79 (18H, CH2C6H5COCH2CO), 4.25–4.41
(18H, CH2CHOCH2CO), 4.16 (8H, C6H5CH2OCH2), 3.92–3.96
(3H, CH). dC (100 MHz, CDCl3) 170.2, 170.1, 169.5, 168.8,
166.9, 166.7, 137.0, 129.0, 128.9, 128.8, 128.7, 128.5, 128.4,
128.3, 128.2, 128.1, 77.4, 77.2, 77.0 76.7, 76.0, 75.8, 73.6, 73.4,
69.1, 67.3, 67.2, 67.1, 66.7, 65.4, 65.3, 64.0, 63.7, 63.2, 61.2,
60.5. m/z (MALDI-TOF) Calc. for C61H68O31: 1296. Found:
1335 (M þ K)þ, 1373 (M þ Kþ þ Kþ ꢀ H).
Synthesis of Dendron G1COOH
Dendron G1 (5 g, 8.93 mmol) was dissolved in 20 mL anhy-
drous CH2Cl2. The solution was chilled to room temperature and
treated with TFA (15 mL) and triethylsilane (1 mL). After
stirring for 2 h, TFA and CH2Cl2 were removed under reduced
pressure. The residue was dissolved in saturated aqueous sodium
bicarbonate, and extracted with dichloromethane two times.
Removing the organic extract, the aqueous layer (adjusted to pH
3.0 with 1 M HCl) was extracted with dichloromethane three
times and the extracts were dried over MgSO4. The product was
obtained by removal of the solvent from the dried extract. dH
(400 MHz, CDCl3) 7.32–7.38 (10H, C6H5), 4.65–4.69 (4H,
CH2C6H5CH2COOH), 4.16–4.41 (6H, CH2CHOCH2CO), 4.16
(4H, C6H5CH2OCH2CO), 3.93–3.96 (1H, CH). dC (100 MHz,
CDCl3) 170.4, 170.1, 169.4, 136.9, 128.5, 128.0, 75.9, 73.4,
67.1, 63.2, 60.3. m/z (MALDI-TOF) Calc. for C133H148O71: 502.
Found: 543 (M þ K)þ, 581 (M þ Kþ þ Kþ ꢀ H).
Synthesis of Dendron G3
In a flask equipped with a magnetic stirrer were placed
dendrons G1OH (0.4 g, 1.05 mmol), G2COOH (3.0 g,
2.31 mmol) and 10 mL dichloromethane; DMAP (cat.) and
DCC (0.46 g, 2.31 mmol) were added. Stirring at 08C was
continued for 24 h. The DCC-urea was filtered off and washed
with a small amount of dichloromethane and the filtrate was
evaporated. The crude product was purified by silica gel
chromatography (ethyl acetate/hexane 3 : 1) to yield 3.49 g of
a colourless liquid (90 % yield). dH (400 MHz, CDCl3) 7.26–
7.35 (40H, C6H5), 4.54–4.78 (42H, CH2C6H5COCH2CO),
4.24–4.38 (42H, CH2CHOCH2CO), 4.09–4.19 (16H,
C6H5CH2OCH2), 3.91–3.92 (7H, CH), 1.46 (9H, C(CH3)3). dC
(100 MHz, CDCl3) 170.0, 169.4, 166.7, 166.6, 166.2, 137.2,
129.8, 128.5, 128.4, 128.3, 128.2, 128.1, 127.9, 127.7, 82.6,
75.9, 75.6, 73.3, 67.2, 67.1, 67.0, 63.7, 63.5, 63.1, 61.3, 61.0,
60.6, 60.4, 28.0. m/z (MALDI-TOF) Calc. for C137H156O71:
2936. Found: 2979 (M þ K)þ.
Synthesis of Dendron G1OH
In a flask equipped with a magnetic stirrer, Pd/C (10 % w/w)
was added to a solution of dendron G1 (2 g, 3.57 mmol) in
EtOAc/MeOH (3 : 1, 40 mL). The flask was evacuated and filled
with 2.9 MPa of H2 before shaking for 20 min. The catalyst was
filtered off and washed with EtOAc (10 mL). The filtrate was
then evaporated to give 1.22 g of a colourless viscous oil. dH
(400 MHz, CDCl3) 4.59 (2H, COCH2CO), 4.24–4.39 (6H,
CH2CHOCH2CO), 4.08–4.14 (4H, HOCH2CO), 3.92–3.95
(1H, CH), 1.49 (9H, C(CH3)3). dC (100 MHz, CDCl3) 172.8,
169.5, 166.3, 83.0, 75.9, 67.2, 63.7, 61.3, 60.6, 60.3, 28.0. m/z
(MALDI-TOF) Calc. for C25H28O11: 380. Found: 419
(M þ K)þ.
Synthesis of Dendron G3COOH
In a flask equipped with a magnetic stirrer, dendron G3 (1 g,
0.35 mmol) was dissolved in 10 mL anhydrous CH2Cl2. The
solution was chilled to room temperature and treated with TFA
(10 mL) and triethylsilane (0.5 mL). After stirring for 2 h, TFA
and dichloromethane were removed under reduced pressure.
The crude product was purified by silica gel chromatography
(ethyl acetate/hexane 3 : 1) to yield 0.9 g of a colourless liquid
(95 % yield). dH (400 MHz, CDCl3) 7.26–7.34 (40H, C6H5),
4.62–4.78 (42H, CH2C6H5COCH2CO), 4.24–4.56 (42H,
CH2CHOCH2CO), 4.12–4.15 (16H, C6H5CH2OCH2), 3.95
(7H, CH). dC (100 MHz, CDCl3) 171.2, 170.1, 169.4, 169.2,
166.8, 166.7, 137.0, 129.9, 128.5, 128.3, 127.7, 127.4, 76.7,
75.8, 75.7, 73.6, 73.4, 67.2, 67.1, 67.0, 63.8, 63.4, 63.2, 61.1,
60.8, 60.4, 60.4. m/z (MALDI-TOF) Calc. for C133H148O71:
2882.6. Found: 2919 (M þ K)þ, 2958 (M þ Kþ þ Kþ ꢀ H).
Synthesis of Dendron G2
In a flask equipped with a magnetic stirrer were placed
dendrons G1OH (1.0 g, 2.63 mmol), G1COOH (2.92 g,
5.79 mmol) and 30 mL dichloromethane; DMAP (cat.) and
DCC (1.19 g, 5.79 mmol) were added. Stirring was continued
for 24 h at room temperature. The DCC-urea was filtered off
and washed with a small amount of dichloromethane and the
filtrate was evaporated. The crude product was purified by
silica gel chromatography to yield 3.2 g of a colourless liquid
(90 % yield). dH (400 MHz, CDCl3) 7.31–7.37 (20H, C6H5),
4.56–4.78 (18H, CH2C6H5COCH2CO), 4.19–4.38 (18H,
CH2CHOCH2CO), 4.09–4.13 (16H, C6H5CH2OCH2), 3.92
(3H, CH). dC (100 MHz, CDCl3) 170.0, 169.4, 166.7, 166.6,
166.2, 137.1, 128.5, 128.3, 82.8, 75.9, 75.6, 73.4, 67.2, 67.1,
67.0, 63.7, 63.1, 61.03, 60.4, 28.0. m/z (MALDI-TOF) Calc. for
C65H76O13: 1352. Found: 1391 (M þ K)þ.
Synthesis of Dendrons MPEG-G3 Dendritic
In a flask equipped with a magnetic stirrer were placed
MPEG5000 (0.70 g, 0.14 mmol), dendron G3COOH (0.8 g,
0.28 mmol) and 5 mL dichloromethane; DMAP (cat.) and
DCC (0.058 g, 0.28 mmol) were added. Stirring at 08C was
continued for 24 h. The DCC-urea was filtered off and washed
with a small amount of dichloromethane and the filtrate was
evaporated. Anhydrous ether was added dropwise to the crude
product to precipitate the products; this was repeated twice, and
the precipitate was filtered off and vacuum-dried to yield 0.99 g
of a white powder (81 % yield). dH (400 MHz, CDCl3) 7.26–7.35
(40H, C6H5), 4.62–4.76 (42H, CH2C6H5COCH2CO), 4.24–4.34
(42H, CH2CHOCH2CO), 4.13 (16H, C6H5CH2OCH2), 3.92
(7H, CH), 3.64 (CH2CH2O), 3.38 (3H, CH3O). dC (100 MHz,
CDCl3) 170.0, 69.4, 137.1, 128.5, 128.0, 75.8, 75.7, 73.4, 70.6,
67.32, 67.1, 63.7, 63.1. m/z (MALDI-TOF) Calc. for: 7925.
Found: 7791 (M þ K)þ.
Synthesis of Dendron G2COOH
In a flask equipped with a magnetic stirrer, dendron G2 (3 g,
2.22 mmol) was dissolved in 20 mL anhydrous dichloro-
methane. The solution was chilled to room temperature and
treated with TFA (15 mL) and triethylsilane (1 mL). After
stirring for 2 h, TFA and dichloromethane were removed under
reduced pressure. The crude product was purified by silica gel
chromatography (ethyl acetate/hexane 2 : 1) to yield 2.59 g of
colourless liquid (90 % yield). dH (400 MHz, CDCl3) 7.33–7.38

Amphiphilic Dendritic Polyether-ester
551
Acknowledgements
[10] M. W. Grinstaff, Chemistry 2002, 13, 2839.
[11] H. Ihre, A. Hult, E. So1derlind, J. Am. Chem. Soc. 1996, 118, 6388.
doi:10.1021/JA954171T
[12] O. L. P. D. Jesu´s, H. R. Ihre, L. Gagne, J. M. J. Fre´chet, F. C. Szoka,
Financial support was provided by the National Natural Science Foundation
of China (NSFC20804032) and Scientific Research Fund of Hunan
Provincial Education Department (09K038).
Bioconjug. Chem. 2002, 13, 453.
[13] (a) M. A. Carnahan, M. W. Grinstaff, Macromolecules 2001, 34, 7648.
doi:10.1021/MA010848N
(b) N. R. Luman, K. A. Smeds, M. W. Grinstaff, Chemistry 2003, 9,
5618. doi:10.1002/CHEM.200305172
[14] (a) E. R. Gillies, E. Dy, J. M. J. Fre´chet, F. C. Szoka, Mol. Pharm. 2005,
References
[1] D. A. Tomalia, A. M. Naylor, W. A. Goddard, Angew. Chem. Int. Ed.
Engl. 1990, 29, 138. doi:10.1002/ANIE.199001381
[2] M. T. Morgan, M. A. Carnahan, C. E. Immoos, A. A. Ribeiro,
S. Finkelstein, S. J. Lee, M. W. Grinstaff, J. Am. Chem. Soc. 2003,
125, 15485. doi:10.1021/JA0347383
2, 129. doi:10.1021/MP049886U
(b) M. A. Carnahan, C. Middleton, J. Kim, T. Kim, M. W. Grinstaff,
J. Am. Chem. Soc. 2002, 124, 5291. doi:10.1021/JA025576Y
(c) K. Xiao, J. Luo, W. L. Fowler, Y. Li, J. S. Lee, L. Xing,
R. H. Cheng, L. Wang, K. S. Lam, Biomaterials 2009, 30, 6006.
doi:10.1016/J.BIOMATERIALS.2009.07.015
[3] (a) M. E. Piotti, F. Rivera, C. J. Hawker, J. M. J. Fre´chet, J. Am. Chem.
Soc. 1999, 121, 9471. doi:10.1021/JA991879P
(b) C. Francavilla, M. D. Drake, F. V. Bright, M. R. Detty, J. Am.
Chem. Soc. 2001, 123, 57. doi:10.1021/JA002649þ
[4] (a) Z. Peng, Y. Pan, B. Xu, J. Zhang, J. Am. Chem. Soc. 2000, 122,
6619. doi:10.1021/JA0006907
[15] (a) T. C. Stover, Y. S. Kim, T. L. Lowe, M. Kester, Biomaterials 2008,
29, 359. doi:10.1016/J.BIOMATERIALS.2007.09.037
(b) P. M. Nguyen, P. T. Hammond, Langmuir 2006, 22, 7825.
doi:10.1021/LA0607050
(b) M. J. Xiong, Z. H. Li, M. S. Wong, Aust. J. Chem. 2007, 60, 603.
doi:10.1071/CH07038
(c) F. Chen, P. Akhtar, L. A. P. Kane-Maguire, G. G. Wallace, Aust.
J. Chem. 1997, 50, 939. doi:10.1071/C96189
[16] E. R. Gillies, T. B. Jonsson, J. M. J. Fre´chet, J. Am. Chem. Soc. 2004,
126, 11936. doi:10.1021/JA0463738
[5] (a) K. C. Wood, S. R. Little, R. Langer, P. T. Hammond, Angew. Chem.
Int. Ed. 2005, 44, 6704. doi:10.1002/ANIE.200502152
(b) D. Luo, K. Haverstick, N. Belcheva, E. Han, W. M. Saltzman,
Macromolecules 2002, 35, 3456. doi:10.1021/MA0106346
[6] (a) C. C. Lee, E. R. Gillies, M. E. Fox, S. J. Guillaudeu, J. M. J. Fre´chet,
E. E. Dy, F. C. Szoka, Proc. Natl. Acad. Sci. USA 2006, 103, 16649.
doi:10.1073/PNAS.0607705103
[17] M. A. Carnahan, M. W. Grinstaff, J. Am. Chem. Soc. 2001, 123, 2905.
doi:10.1021/JA005726þ
[18] (a) P. G. Parzuchowski, M. Grabowska, M. Tryznowski, G. Rokicki,
Macromolecules 2006, 39, 7181. doi:10.1021/MA061488C
(b) X. H. Yu, J. Feng, R. X. Zhuo, Macromolecules 2005, 38, 6244.
doi:10.1021/MA048839C
[19] L. Zhang, J. Fu, Z. Xia, P. Wu, X. Zhang, J. Appl. Polym. Sci. 2011,
(b) C. K. Y. Chun, R. J. Payne, Aust. J. Chem. 2009, 62, 1339.
doi:10.1071/CH09282
[7] E. R. Gillies, J. M. J. Fre´chet, Drug Discov. Today 2005, 10, 35.
doi:10.1016/S1359-6446(04)03276-3
[8] (a) S. Svenson, D. A. Tomalia, Adv. Drug Deliv. Rev. 2005, 57, 2106.
doi:10.1016/J.ADDR.2005.09.018
(b) U. Gupta, H. B. Agashe, A. Asthana, N. K. Jain, Biomacromole-
cules 2006, 7, 649. doi:10.1021/BM050802S
[9] S. H. Medina, M. E. H. El-Sayed, Chem. Rev. 2009, 109, 3141.
doi:10.1021/CR900174J
122, 758. doi:10.1002/APP.33871
[20] J. Jiang, L. Zhang, M. Wu, X. Zhang, J. Control. Release 2011, 152,
e192. doi:10.1016/J.JCONREL.2011.09.002
[21] B. Romagnoli, P. R. Ashton, L. M. Harwood, D. Philp, D. W. Price,
M. H. Smith, W. Hayes, Tetrahedron 2003, 59, 3975. doi:10.1016/
S0040-4020(03)00466-6
[22] N. Baggett, J. S. Brimacombe, A. B. Foster, M. Stacey, D. H. Whiffen,
J. Chem. Soc. 1960, 2574. doi:10.1039/JR9600002574