Dendron-polymer conjugates via the diels-alder click reaction of novel anthracene-based dendrons

Article abstract of DOI:10.1002/pola.26708

Diblock and triblock dendron-polymer conjugates containing biodegradable polyester dendron blocks and polyethylene glycol (PEG) polymer were synthesized using the Diels-Alder click cycloaddition reaction. PEG polymers with furan-protected maleimide functionality were synthesized and reacted with biodegradable polyester dendrons containing an anthracene moiety at their focal point. First through third generations of biodegradable polyester dendrons containing an anthracene unit at their focal point were synthesized using a divergent strategy. Efficient conjugation of the dendrons to polymers was demonstrated using ¹HNMR and size exclusion chromatography. This modular approach provides an easy access to the design of multivalent PEG conjugates.

Full text of DOI:10.1002/pola.26708

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Dendron–Polymer Conjugates via the Diels–Alder “Click” Reaction of
Novel Anthracene-Based Dendrons
Ozgul Gok, Sezin Yigit, Meliha Merve Kose, Rana Sanyal, Amitav Sanyal
Department of Chemistry, Bogazici University, Bebek, Istanbul 34342, Turkey
Correspondence to: A. Sanyal (E-mail: amitav.sanyal@boun.edu.tr) or R. Sanyal (E-mail: rana.sanyal@boun.edu.tr)
Received 16 February 2013; accepted 26 March 2013; published online 19 April 2013
DOI: 10.1002/pola.26708
ABSTRACT: Diblock and triblock dendron–polymer conjugates
containing biodegradable polyester dendron blocks and poly-
ethylene glycol (PEG) polymer were synthesized using the
Diels–Alder “click” cycloaddition reaction. PEG polymers with
furan-protected maleimide functionality were synthesized and
reacted with biodegradable polyester dendrons containing an
anthracene moiety at their focal point. First through third gener-
ations of biodegradable polyester dendrons containing an an-
thracene unit at their focal point were synthesized using a
divergent strategy. Efficient conjugation of the dendrons to
polymers was demonstrated using 1HNMR and size exclusion
chromatography. This modular approach provides an easy
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2013, 51, 3191–3201
KEYWORDS: anthracene; block copolymers; click cycloaddition;
dendrimers; dendronized polymers; Diels-Alder polymers
multivalency of PEG by introduction of branching at the side
chain or chain ends.27–32 This can be achieved by introduc-
tion of well-defined dendritic end-groups.33–36 Usually, the
method employed for the synthesis of dendron polymer con-
jugates involves growth of the dendrons by using the PEG
diol-based macroinitiator.37,38 Novel modular approaches to-
ward both polymer synthesis and modification have
attracted great attention owing to the advantages offered by
such processes. Recently, dendron–polymer–dendron conju-
gates were synthesized via Huisgen-type click cycloaddi-
tion39–43 between telechelic azide groups containing PEG
with polyester dendrons containing alkyne group at their
focal point.44 It was shown that such dendron–polymer con-
jugates can be utilized to fabricate functionalizable hydro-
gels.45,46 In recent years, the Diels–Alder reaction has
attracted considerable attention as a powerful metal-free
conjugation reaction and to obtain a wide variety of discrete
macromolecular constructs efficiently.47–53
INTRODUCTION Attachment of proteins, peptides, and small
drug molecules to appropriate polymeric supports has dem-
onstrated increase in their therapeutic value by addressing
challenges such as poor solubility, rapid excretion, and non-
targeted delivery.1–4 Over the past decades, owing to major
advancements in the area of drug delivery via conjugation of
therapeutic materials to polymers, “polymer therapeutics”
has emerged as a discipline.5–9 Increased in vivo efficacy of
polymer conjugates observed owing to enhanced permeation
and retention effect, which is preferential uptake and accu-
mulation of macromolecular entities in tumor owing to leaky
vasculature, is one of the key advantages of polymer drug
conjugates.10–13 One of the most widely explored polymeric
supports in this regard has been polyethylene glycol
(PEG).14,15 Although the attachment to PEG or PEGylation
offers several advantages such as increased bioavailability,
reduced toxicity, and prolonged residence time in the
body,16–18 one of the major limitations of using linear PEG
polymer as a support is its low loading capacity. One alterna-
tive approach to address this problem is to employ branched
PEG, that is multiarmed PEGs.19–21 In this regard, recent
years have witnessed an increasing interest in the synthesis
of well-defined biocompatible and preferably biodegradable
polymeric supports owing to their potential drug delivery
agents.22–26 As opposed to their linear counterparts, these
are more expensive and usually have higher polydispersities.
Another approach that has been evaluated is to increase the
Herein, we report the synthesis of novel dendron–polymer
conjugates that allow facile access to multivalent PEG poly-
mers using the Diels–Alder cycloaddition reaction. Novel bio-
degradable polyester dendrons containing an electron-rich
anthracene group at their focal point and hydroxyl groups at
their periphery were synthesized. These dendrons were
reacted with either mono-functional or telechelic linear PEG
polymers containing furan-protected maleimide group at
Additional Supporting Information may be found in the online version of this article.
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chain ends to furnish diblock and triblock copolymers,
respectively. Thus, reagent-free thermal Diels–Alder cycload-
dition provides facile access to linear-PEG polymers contain-
ing several hydroxyl functional groups at chain ends for
further functionalization (Fig. 1).
RID-10A refractive index detector and PLgel (length/ID 8 3
300 mm, 10 mm particle size) Mixed-B columns was also used
to obtain some of the molecular weights and molecular
weight distributions. THF was used as mobile phase (1 mL/
ꢀ
min, 30 C) using a Shimadzu LC20AD pump.
Synthesis of First-Generation Anthracene-Functionalized
Dendron (2)
EXPERIMENTAL
Materials and Instrumentation
Compound 1 was synthesized according to the previously
reported literature procedures.57,58 To a solution of anhy-
dride 1 (4.25 g, 12.86 mmol) in CH2Cl2 (40 mL), 9-anthra-
cene methanol (1.79 g, 8.58 mmol), 4-dimethylaminopyridine
(DMAP) (0.42 g, 3.43 mmol), and pyridine (2.50 mL) were
added. The mixture was stirred at room temperature for 20
h followed by quenching of excess anhydride with (1:1) mix-
ture of pyridine and water (8.20 mL) for 5 h. Reaction mix-
ture was extracted with 1 M of NaHSO4 (3 3 60 mL), 10%
of Na2CO3 (3 3 60 mL), and then with brine (1 3 60 mL).
The combined organic layers were dried over anhydrous
Na2SO4. The residue was concentrated in vacuo. The product
was obtained as a yellow solid (5.70 g, 90% yield). The
obtained solid (2.00 g, 5.30 mmol) was dissolved in MeOH
(30 mL) and to this solution Dowex H1 resin was added
with a tip of spatula. The resulting mixture was stirred at
room temperature until the consumption of starting material
was observed via TLC. The resin was then filtered off and
washed with MeOH. The crude product was purified by
recrystallization with CHCl3. The product was obtained by fil-
tration to give 2 as a yellow solid (1.78 g, 99% yield).
All reagents were obtained from commercial sources (Merck,
Aldrich, and Alfa Aesar) and were used as received unless
otherwise stated. Dry solvents (CH2Cl2, tetrahydrofuran [THF],
and toluene) were obtained from ScimatCo Purification Sys-
tem and other dry solvents were dried over molecular sieves.
Column chromatography was performed using silicagel-60
(43–60 nm). Thin-layer chromatography (TLC) was performed
using silica gel plates (Kiesel gel 60 F254, 0.2 mm, Merck).
Plates were viewed under 254 nm UV lamp otherwise plates
were developed by KMnO4 stain. Acetonide-2,2-bis(methoxy)-
propionic anhydride (1) was prepared according to the previ-
ously published literature procedures.55,56 PEG diol (2K) and
monomethoxy PEG (2K) were dried under vacuum after azeo-
tropic distillation with toluene. The dendron and polymer
characterizations involved 1HNMR spectroscopy (Varian, 400
MHz) at the Advanced Technologies Research and Develop-
ment Center at Bogazici University, FlashEAR 1112 Series Ele-
mental Analyzer (CHNS Separation Column, PTFE; 2 m; 6 3
5 mm) and Fourier transform infrared (ATR-FTIR) spectros-
copy (Thermo Fisher Scientific, Nicolet 380). The molecular
weights were estimated by a gel permeation chromatography
(GPC) analysis using a Viscotek GPCmax VE-2001 analysis sys-
tem. PLgel (length/ID 300 mm 3 7.5 mm, 5 mm particle
size) Mixed-C column was calibrated with polystyrene stand-
ards (1–150K), using refractive index detector. THF was used
as the eluent at a flow rate of 1 mL/min at 30 ꢀC. A size
exclusion chromatography system equipped with a Shimadzu
1HNMR (CDCl3, d, ppm) 8.51 (s, 1H, ArH), 8.30 (d, 2H,
J 5 8.4 Hz, ArH), 8.03 (d, 2H, J 5 8.4 Hz, ArH), 7.57 (dd, 2H,
J 5 8,4, 6.4 Hz, ArH), 7.49 (dd, 2H, J 5 8,4, 6.4 Hz, ArH),
6.21 (s, 2H, CH2AAr), 3.85 (d, 2H, J 5 11.2 Hz, OCH2), 3.66
(d, 2H, J 5 11.2 Hz, OCH2), 2.68 (br s, 2H, OH), 0.97 (s, 3H,
C(CH3)). 13CNMR (CDCl3, d, ppm) 176.1, 131.3, 131.0, 129.4,
129.2, 126.8, 125.7, 125.2, 123.7, 68.4, 59.7, 49.4, 17.1. Anal.
calcd. for G1-anthracene dendron [C20H20O4]: C, 74.06; H,
6.21; O, 19.73. Found: C, 74.25; H, 6.44; O, 19.31.
Synthesis of Second-Generation Anthracene-Functionalized
Dendron (3)
Compound 2 (0.32 g, 0.99 mmol) was added to a solution of
DMAP (0.06 g, 0.49 mmol), pyridine (0.72 mL), and com-
pound 1 (1.14 g, 3.45 mmol) in CH2Cl2 (10 mL). The mixture
was then stirred at room temperature for 20 h followed by
quenching of excess anhydride with (1:1) mixture of pyridine
and water (2.40 mL) for 5 h. Reaction mixture was diluted
with CH2Cl2 (30 mL) and extracted with 1 M of NaHSO4 (3
3 40 mL), 10% of Na2CO3 (3 3 40 mL), and then with
brine (1 3 40 mL). The combined organic layers were dried
over anhydrous Na2SO4. The residue was concentrated in
vacuo. Crude product was purified by column chromatogra-
phy to give a yellow solid (0.48 g, 76% yield). Obtained com-
pound (0.48 g, 0.76 mmol) was dissolved in MeOH (18 mL)
and to this solution Dowex H1 resin was added with a tip
of spatula. The resulting mixture was stirred at room tem-
perature until the consumption of starting material was
FIGURE 1 Synthesis of dendron–polymer block copolymers via
the Diels–Alder “click” reaction.
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observed via TLC. The resin was then filtered off and washed
with MeOH. Crude product was purified by column chroma-
tography to give 3 as a yellow solid (0.38 g, 91% yield).
under N2. The crude was concentrated and precipitated in
cold diethyl ether. The product was filtered and dried under
vacuum. The precipitation procedure was repeated twice to
give pure mono-acid PEG as white solid 5 (1.95 g, 93%
yield). Then, polymer 5 (1.50 g, 0.71 mmol) was dried under
vacuum after azeotropic distillation with toluene. To a solu-
tion of 5 dissolved in CH2Cl2 (10 mL), the furan-protected
maleimide group containing alcohol (6) (0.49 g, 2.14 mmol),
DMAP (0.09 g, 0.07 mmol), and EDCI (0.15 g, 0.78 mmol)
were added. The solution was stirred for 20 h at room tem-
perature under N2. To the reaction mixture, CH2Cl2 (20 mL)
was added and the mixture was washed with saturated
NaHCO3 (2 3 15 mL). The combined organic layers were
dried over anhydrous Na2SO4 and all volatiles were evapo-
rated. After precipitating twice in cold diethyl ether, pure
mono-maleimide PEG was filtered and dried under vacuum
as a white solid 7 (1.22 g, 75% yield).
1HNMR (CDCl3, d, ppm) 8.51 (s, 1H, ArH), 8.32 (d, 2H,
J 5 8.8 Hz, ArH), 8.02 (d, 2H, J 5 8.8 Hz, ArH), 7.57 (dd, 2H,
J 5 8.8, 7.6 Hz, ArH), 7.49 (dd, 2H, J 5 8.8, 7.6 Hz, ArH),
6.23 (s, 2H, CH2AAr), 4.34 (d, 2H, J 5 11.2 Hz, CH2 ester
protons), 4.22 (d, 2H, J 5 11.2 Hz, CH2 ester protons), 3.70–
3.51 (m, 8H, OCH2), 2.90–2.86 (m, 4H, OH), 1.25 (s, 3H,
C(CH3)), 0.80 (s, 6H, C(CH3)). 13CNMR (CD3COD, d, ppm)
175.9, 175.6, 132.9, 132.4, 130.5, 131.2, 127.9, 127.2, 126.3,
125.1, 66.5, 65.8, 64.4, 60.7, 51.7, 18.2, 17.2. Anal. calcd. for
G2-anthracene dendron [C30H36O10]: C, 63.44; H, 6.61; O,
29.95. Found: C, 63.52; H, 6.82; O, 29.66.
Synthesis of Third-Generation Anthracene-Functionalized
Dendron (4)
1HNMR (CDCl3, d, ppm) 6.48 (s, 2H, CH@CH), 5.23 (s, 2H, CH
bridgehead protons), 4.22 (t, 2H, J 5 4.8 Hz, OCH2), 4.03 (t,
2H, J 5 6.4 Hz, NCH2), 3.82–3.41 (m, 4H, OCH2CH2 of PEG),
3.35 (s, 3H, OCH3 of PEG), 2.82 (s, 2H, CH-CH bridge pro-
tons), 2.69–2.60 (m, 4H, CH2C@O), 1.89 (tt, 2H, J 5 6.0, 4.8
Hz, NCH2CH2CH2O).
Compound 3 (0.40 g, 0.72 mmol) was added to a solution of
DMAP (0.19 g, 1.55 mmol), pyridine (2.70 mL), and com-
pound 1 (1.90 g, 5.75 mmol) in CH2Cl2 (18 mL). The mixture
was then stirred at room temperature for 20 h. Excess anhy-
dride was quenched with (1:1) mixture of pyridine and water
(9 mL) for 5 h. Reaction mixture was diluted with CH2Cl2 (20
mL) and then extracted with 1 M of NaHSO4 (3 3 40 mL),
10% of Na2CO3 (3 3 40 mL), and then with brine (1 40
mL). The combined organic layers were dried over anhydrous
Na2SO4. The residue was concentrated in vacuo. The product
was obtained as a pure light yellow solid (0.83 g, 98% yield).
Thus obtained compound (0.83 g, 0.71 mmol) was dissolved
in MeOH (20 mL) and to this solution Dowex H1 resin was
added with a tip of spatula. The resulting mixture was stirred
Synthesis of Bis-Maleimide PEG (9)
To a solution of dried PEG (2 g, 1 mmol) dissolved in THFꢀ(5
mL), triethylamine (0.42 mL, 2.99 mmol) was added at 0 C.
In a separate flask, succinic anhydride (0.34 g, 3.42 mmol)
and DMAP (0.05 g, 0.40 mmol) were dissolved in THF (5
ꢀ
mL) and transferred drop wise onto the PEG solution at 0 C
for more than 30 min. The clear solution was stirred for 20
h at room temperature under N2. The crude was concen-
trated and precipitated in cold diethyl ether. The product
was filtered and dried under vacuum. The precipitation pro-
cedure was repeated twice to give pure bis-acid PEG as
white solid 8 (2.13 g, 97% yield). Then, polymer 8 (1.50 g,
0.68 mmol) was dried under vacuum after azeotropic distil-
lation with toluene. To a solution of 1a dissolved in CH2Cl2
(15 mL), the furan-protected maleimide group containing
alcohol (6) (0.90 g, 4.10 mmol), DMAP (0.016 g, 0.14 mmol),
and EDCI (0.29 g, 1.49 mmol) were added. The solution was
stirred for 20 h at room temperature under N2. To the reac-
tion mixture, CH2Cl2 (30 mL) was added and the mixture
was washed with saturated NaHCO3 (2 3 30 mL). The com-
bined organic layers were dried over anhydrous Na2SO4 and
all volatiles were evaporated. After precipitating twice in
cold diethyl ether, pure bis-maleimide PEG was filtered and
dried under vacuum as a white solid 9 (1.40 g, 79% yield).
at room temperature until the consumption of
4 was
observed via TLC. The resin was then filtered off and washed
with MeOH. The crude product was purified by recrystalliza-
tion with CHCl3. The product was obtained by filtration to
give 7 as a yellow solid (0.68 g, 95% yield).
1HNMR (CD3COD, d, ppm) 8.56 (s, 1H, ArH), 8.42 (d, 2H,
J 5 8.8 Hz, ArH), 8.06 (d, 2H, J 5 8.4 Hz, ArH), 7.60 (dd, 2H,
J 5 8.8, 6.8 Hz, ArH), 7.50 (dd, 2H, J 5 8.8, 6.8 Hz, ArH),
6.26 (s, 2H, CH2AAr), 4.58 (br s, 8H, OH), 4.28–4.05 (m,
16H, CH2 ester protons), 3.65 (d, 8H, J 5 10.8 Hz, OCH2 pro-
tons), 3.58 (d, 8H, J 5 10.8 Hz, OCH2 protons),1.23 (s, 3H,
C(CH3)), 1.12 (s, 12H, C(CH3)), 0.99 (s, 6H, C(CH3)). 13CNMR
(CD3COD, d, ppm) 183.6, 181.7, 181.4, 140.5, 140.1, 139.0,
138.3, 136.8, 135.4, 134.6, 133.8, 74.2, 73.9, 73.6, 73.2, 72.8,
59.9, 56.0, 55.8, 26.7, 25.9. Anal. calcd. for G3-anthracene
dendron [C50H68O22]: C, 57.64; H, 6.80; O, 35.56. Found: C,
57.65; H, 6.55; O, 35.80.
1HNMR (CDCl3, d, ppm) 6.48 (s, 2H, CH@CH), 5.23 (s, 2H, CH
bridgehead protons), 4.22 (t, 2H, J 5 4.8 Hz, OCH2), 4.03 (t,
2H, J 5 6.0 Hz, NCH2), 3.80–3.42 (m, 4H, OCH2CH2 of PEG),
2.82 (s, 2H, CHACH bridge protons), 2.67–2.59 (m, 4H,
CH2C@O), 1.90 (tt, 2H, J 5 6.0, 4.8 Hz, NCH2CH2CH2O).
Synthesis of Mono-Maleimide PEG (7)
To a solution of dried monomethoxy PEG (2.00 g, 1 mmol)
dissolved in THF (5 mL), triethylamine (0.21 mL, 1.50
ꢀ
mmol) was added at 0 C. In a separate flask, succinic anhy-
dride (0.17 mg, 1.70 mmol) and DMAP (0.024 mg, 0.20
mmol) were dissolved in THF (5 mL) and transferred drop
wise onto the PEG solution at 0 ꢀC for more than 30 min.
The clear solution was stirred for 20 h at room temperature
General Procedure for Diblock Copolymer Synthesis
Mono-maleimide PEG (7) (0.20 g, 0.09 mmol) and G3-an-
thracene dendron (4) (0.092 g, 0.09 mmol) were dissolved
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in toluene (4 mL) and the mixture was heated under nitro-
gen at 110 ꢀC for 6 h. Then, all volatiles were removed in
vacuo and after precipitating twice in cold diethyl ether, the
product was filtered and dried under vacuum to give P3 as
a light yellow solid (0.22 g, 77% yield).
C(CH3)), 1.15 (d, 6H, J 5 5.6 Hz, C(CH3)). FTIR (cm2 1):
3437, 2882, 1732, 1698.
1HNMR data for copolymer P6: (CDCl3, d, ppm) 7.36–7.10
(m, 8H, ArH), 5.56–5.35 (m, 2H, CH2OC@O), 4.72 (s, 1H, CH
bridgehead protons), 4.32–4.18 (m, 16H, OCH2, NCH2, and
CH2 ester protons), 3.75–3.52 (m, 28H, OCH2CH2 of PEG, CH2
ester protons, and OH), 3.44–3.40 (m, 4H, NCH2CH2CH2O),
3.28–3.10 (m, 2H, CHACH bridge protons), 2.58–2.52 (m, 4H,
O@CACH2CH2AC@O), 1.26 (s, 3H, C(CH3)), 1.22 (d, 6H, J 5
10.4 Hz, C(CH3)), 1.01 (d, 12H, J 5 2.8 Hz, C(CH3)).
1HNMR data for copolymer P1: (CDCl3, d, ppm) 7.39–7.29
(m, 4H, ArH), 7.19–7.16 (m, 4H, ArH), 5.54–5.42 (m, 2H,
CH2OC@O), 4.77 (s, 1H, CH bridgehead proton), 4.22 (t, 2H, J
5 4.4 Hz, OCH2), 3.90–3.83 (m, 4H, CH2 ester protons), 3.79
(t, 2H, J 5 4.8 Hz, NCH2), 3.70–3.58 (m, 4H, OCH2CH2 of
PEG), 3.49–3.42 (m, 2H, NCH2CH2CH2O), 3.35 (s, 3H, OCH3
of PEG), 3.28 (br s, 1H, CHACH bridge proton), 3.18 (t, 1H,
J 5 6.8 Hz, CHACH bridge proton), 2.97 (br s, 2H, OH), 2.64–
2.55 (m, 4H, O@CACH2CH2AC@O), 1.12 (s, 3H, C(CH3)).
Alkyne Functionalization of P5
Copolymer G2-PEG-G2 (P5) (0.30 g, 0.08 mmol), pyridine
(0.27 mL), and DMAP (0.016 g, 0.13 mmol) were dissolved
in dry CH2Cl2 (5 mL) in a 10-mL round-bottom flask. To the
stirring reaction mixture, 5-pentyonic acid anhydride (0.18 g,
1.01 mmol) was added and the solution was stirred for 20 h
at room temperature under N2. Then, pyridine:water solution
(0.6 mL, 1:1) was added to the reaction mixture and stirred
at room temperature for 1 h. Reaction mixture was diluted
with CH2Cl2 (20 mL) and then extracted with 1 M of NaHSO4
(3 3 20 mL), 10% of Na2CO3 (3 3 20 mL), and then with
brine (1 3 20 mL). The combined organic layers were dried
over anhydrous Na2SO4 and the residue was concentrated in
vacuo. Crude product was purified by precipitation in diethyl
ether to give P7 as a white solid (0.21 g, 60% yield).
Mn,theo 5 4219, Mn,GPC 5 4703, Mw/Mn 5 1.15, relative to PS.
1HNMR data for copolymer P2: (CDCl3, d, ppm) 7.34–7.10
(m, 8H, ArH), 5.50–5.40 (m, 2H, CH2OC@O), 4.71 (s, 1H, CH
bridgehead proton), 4.44–4.36 (m, 2H, OCH2), 4.25–4.16 (m,
4H, CH2 ester protons), 3.96–3.90 (m, 2H, NCH2), 3.74–3.39
(m, 18H, OCH2CH2 of PEG, CH2 ester protons, NCH2CH2CH2O,
and OH), 3.30 (s, 3H, OCH3 of PEG), 3.24–3.11 (m, 2H, CHACH
bridge protons), 2.57–2.52 (m, 4H, O@CACH2CH2AC@O), 1.12
(d, 6H, J 5 6.0 Hz, C(CH3)), 1.02 (d, 3H, J 5 4.8 Hz, C(CH3)).
1HNMR data for copolymer P3: (CDCl3, d, ppm) 7.41–7.14
(m, 8H, ArH), 5.62–5.39 (m, 2H, CH2OC@O), 4.76 (d, 1H, J 5
3.2 Hz, CH bridgehead proton), 4.40–4.20 (m, 16H, OCH2, NCH2,
and CH2 ester protons), 3.80–3.13 (m, 35H, OCH2CH2 of PEG,
CH2 ester protons, OCH3 of PEG, NCH2CH2CH2O, CHACH bridge
protons, and OH), 2.63–2.54 (m, 4H, O@CACH2CH2AC@O),
1.31 (s, 3H, C(CH3)), 1.28 (s, 3H, C(CH3)), 1.26 (s, 3H, C(CH3)),
1.05 (s, 6H, C(CH3)).
1H NMR (CDCl3, d, ppm) 7.40–7.14 (m, 8H, ArH), 5.66–5.27
(m, 2H, CH2OC@O), 4.76 (d, 1H, J 5 1 Hz, CH bridgehead
proton), 4.35–4.11 (m, 6H, OCH2, and CH2 ester protons),
3.79 (m, 2H, J 5 4.8 Hz, NCH2), 3.72–3.42 (m, 12H, OCH2CH2
of PEG, CH2 ester protons, and NCH2CH2CH2O), 3.38–3.26 (m,
1H, CHACH bridge protons), 3.21–3.10 (m, 1H, CHACH bridge
protons), 2.62–2.46 (m, 20H, O@CACH2CH2AC@O and
O@CACH2CH2AC[tbond]CH), 1.89 (bs, 4H, C[tbond]H), 1.29–
1.22 (m, 9H, C(CH3)). FTIR (cm2 1): 3276, 2885, 1735, 1700.
General Procedure for Triblock Copolymer Synthesis
Bis-maleimide PEG (9) (0.20 g, 0.08 mmol) and G3-anthra-
cene dendron (4) (0.16 g, 0.15 mmol) were dissolved in tol-
uene (5 mL) and the mixture was heated under nitrogen at
110 ꢀC for 6 h. Then, all volatiles were removed in vacuo
and after precipitating twice in cold diethyl ether, the prod-
uct was filtered and dried under vacuum to give P6 as a
light yellow solid (0.29 g, 84% yield).
Conjugation of Thioglycerol to P7
Alkyne-functionalized G2-PEG-G2 (P7) (10 mg, 2.37
3
102 3 mmol), 5% weight 2,20-dimethoxy-2-phenylacetopho-
none, and thioglycerol (20.50 mg, 0.19 mmol) in 0.1 mL of
DMF were placed in a vial. Then, the vial was purged with
N2 for 10 min and irradiated for 1 h at 365 nm at room tem-
perature. Subsequently, the reaction content was precipitated
in diethyl ether to give P8 as a viscous solid (11.5 mg, 82%
yield). Mn,theo 5 5950, Mn,GPC 5 4600, and Mw/Mn 5 1.23,
relative to PS.
1HNMR data for copolymer P4: (CDCl3, d, ppm) 7.38–7.18
(m, 8H, ArH), 5.54–5.40 (m, 2H, CH2OC@O), 4.76 (s, 1H, CH
bridgehead proton), 4.22 (br s, 2H, OCH2), 3.90–3.79 (m, 6H,
CH2 ester protons, and NCH2), 3.70–3.16 (m, 10 H, CHACH
bridge protons, OCH2CH2 of PEG, NCH2CH2CH2O, and OH),
2.62–2.57 (m, 8H, O@CACH2CH2AC@O), 1.12 (s, 6H,
C(CH3)).
1H NMR (CDCl3, d, ppm) 7.38–7.14 (m, 8H, ArH), 5.62–5.17
(m, 2H, CH2OC@O), 4.74 (s, 1H, CH bridgehead proton),
4.53–4.03 (m, 6H, OCH2, and CH2 ester protons), 3.78 (m,
2H, J 5 4.6 Hz, NCH2), 3.67–3.29 (m, 14H, OCH2CH2 of PEG,
CH2 ester protons, and NCH2CH2CH2O), 3.32–3.27 (m, 2H,
CHACH bridge protons), 3.24–3.09 (m, 4H, CHS), 3.01–2.83
(m, 8H, CH2S), 2.71–2.44 (m, 20H, O@CACH2CH2AC@O, and
O@CACH2CH2-C[tbond]CH), 1.29–1.07 (m, 9H, C(CH3)). FTIR
(cm2 1): 3398, 2868, 1734, 1670.
1HNMR data for copolymer P5: (CDCl3, d, ppm) 7.48–7.25
(m, 8H, ArH), 5.64–5.50 (m, 2H, CH2OC@O), 4.84 (d, 1H, J 5
2.8 Hz, CH bridgehead proton), 4.58–4.50 (m, 2H, OCH2),
4.39–4.30 (m, 4H, CH2 ester protons), 3.90–3.81 (m, 2H,
NCH2), 3.79–3.60 (m, 18H, OCH2CH2 of PEG, CH2 ester pro-
tons, NCH2CH2CH2O, and OH), 3.56–3.51 (m, 1H, CHACH
bridge protons), 3.39–3.23 (m, 1H, CHACH bridge protons),
2.71–2.66 (m, 4H, O@CACH2CH2AC@O), 1.42 (s, 3H,
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an acid resin DOWEXH1 to yield the first-generation
hydroxyl containing dendron (2). Dendron 2 was treated
with the anhydride 1 to yield an acetal-protected dendron
that was deprotected under acidic conditions to yield the
second-generation dendron 3. Similar steps were followed to
obtain third-generation dendron 4.
Polyester dendrons containing peripheral hydroxyl functional
groups were obtained in their pure form via column chroma-
tography and recrystallization. These dendrons were charac-
terized by 1HNMR, 13CNMR, and elemental analysis. In a
typical 1HNMR of a G3 dendron 4, the proton resonances
from the anthracene moiety, the protons adjacent to the
ester group and three methyl groups in the dendron can be
clearly seen around 7.5–9.0, 4.0, and 1.0 ppm, respectively
(Fig. 2).
For the synthesis of diblock and triblock copolymers, PEG
was end-functionalized by furan-protected maleimide groups
(Scheme 2). End-groups of commercially available linear-PEG
polymers were converted to carboxylic acid by treatment
with succinic anhydride in the presence of triethyl amine.54
The carboxylic acid end-groups on the polymers were
reacted with an alcohol bearing a furan-protected maleimide
group. These resultant polymers are referred to as mono-
maleimide PEG (7) and bis-maleimide PEG (9).
SCHEME 1 Divergent synthesis of anthracene-functionalized
polyester dendrons.
RESULTS AND DISCUSSION
Multivalent PEG-based diblock (AB) and triblock (ABA) den-
dron–polymer conjugates were obtained by conjugation of
anthracene-containing dendrons with linear PEG polymers
bearing furan-protected maleimide groups at the chain ends.
Three generations of polyester dendrons bearing an anthra-
cene moiety at the focal point were synthesized as shown in
Scheme 1. Dendrons were synthesized using a divergent
methodology, that is the growth of the repeating units of the
dendron started from the anthracene core toward the pe-
riphery. Reaction of the anhydride 1 with 9-anthraceneme-
thanol yields the first generation acetal-protected dendron
bearing the anthracene group at its core. The acetonide
groups of this dendron were deprotected by treatment with
The desired telechelic PEG polymers were obtained in high
purity as inferred from their 1HNMR spectra. Peaks at 6.48
and 5.23 ppm corresponding to the oxabicyclic moiety
1
observed in HNMR analysis proved the presence of the mal-
eimide group in the structure of bis-maleimide PEG (Fig. 3,
peaks h and g, respectively).
Diblock and triblock copolymers were synthesized by the
Diels–Alder [4 1 2] cycloaddition reaction between the PEG
polymers bearing the masked dienophile and the anthra-
cene-containing polyester dendrons at 110 ꢀC in toluene. At
this temperature, unmasking of the maleimide groups at the
FIGURE 2 1HNMR spectrum of G3-anthracene dendron (4) in CD3OD.
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SCHEME 2 Synthesis of furan-protected maleimide-containing PEG polymers.
polymer chain ends occurs by the removal of furan via the
retro Diels–Alder cycloreversion. The in situ-generated malei-
mide moiety reacts with the anthracene group on the den-
dron (Scheme 3). Reaction of the dendrons with mono-
functional linear-PEG polymer 7 yields diblock copolymers
(Scheme 4), whereas the utilization of telechelic PEG poly-
mer 9 provides the triblock dendron–polymer conjugates
(Scheme 5).
furan–maleimide cycloadduct at the PEG chain termini. Pro-
ton resonances from the aromatic protons owing to the an-
thracene unit can be seen between 7.5 and 7.0 ppm,
whereas the bridgehead proton appears at 4.7 ppm (s, 1H,
and CH bridgehead proton) and the protons on the methylene
unit adjacent to the parent anthracene ring appears around
5.5–5.3 ppm (m, 2H, CH2OC@O) (Figs. 4 and 5, peak f).
The details related to the synthesis and characterization of
the dendron–polymer conjugates are summarized in Table 1.
In all cycloaddition reactions, near-stoichiometric equivalents
Synthesized diblock and triblock copolymers were purified
by precipitation in diethyl ether and characterized by
1HNMR. The Diels–Alder reaction between the maleimide
PEG polymers and the dendrons resulted in the disappear-
ance of peaks at 6.48 and 5.23 ppm belonging to bicyclic
1
of the reactants were used. It was observed by HNMR anal-
ysis that the cycloaddition reaction was fast enough for com-
pletion within 6 h. The yields of the copolymers listed in
FIGURE 3 1HNMR spectra of (bis and mono) furan-protected maleimide polymer.
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SCHEME 3 Diels–Alder reactions to synthesize diblock (P3) and triblock (P6) copolymers.
Table 1 are based on isolated products and any losses are
occurring during precipitation and recovery.
Hydroxyl groups at the periphery of these dendron–polymer
conjugates can be appended with “clickable” functional
groups such as alkene or alkyne units to employ “thiol–ene”
or “thiol–yne” chemistry. Both of these metal-free click reac-
tions have been widely used to conjugate thiol-containing
molecules to polymeric materials.57–60 Here, we demonstrate
that alkyne units can be easily appended and functionalized
to decorate these dendron–polymer conjugates. Functionali-
zation of the hydroxyl groups at the periphery of the triblock
copolymers was obtained via the acylation reaction with
pentyonic anhydride in the presence of pyridine (Scheme 6).
This reaction yielded alkyne-functionalized triblock copoly-
mer (P7). Appearance of a new proton resonances at 1.89
ppm proved the presence of alkyne units in the triblock co-
polymer (Supporting Information Fig. 15S). In the next step,
thioglycerol conjugated these alkyne units via the thiol–yne
reaction under UV-irradiation at 365 nm. The complete dis-
appearance of the alkyne proton resonance at 1.89 ppm and
appearance of new peaks belonging to the thioglycerol moi-
eties around 3.15 and 2.93 ppm indicate near-quantitative
conjugation (Supporting Information Fig. 16S).
SCHEME 4 Structures of diblock dendron–polymer conjugates.
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SCHEME 5 Structures of triblock dendron–polymer–dendron conjugates.
FIGURE 4 1HNMR spectra of G3-dendron (4) in CD3OD, and polymer (7) and dendron–polymer conjugate (P3) in CDCl3.
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FIGURE 5 1HNMR spectra of G3-dendron (4) in CD3OD, and polymer (9) and dendron–polymer conjugate (P6) in CDCl3.
CONCLUSIONS
biodegradable dendrons containing an anthracene unit at their
focal point were synthesized using a divergent growth strat-
egy. Masked maleimide end-capped linear PEG polymers were
used as the hydrophilic component of these triblock copoly-
mers. The metal-free conjugation strategy using these novel
This study provides a new methodology toward ABA-type tri-
block dendron–polymer conjugate synthesis. Diels–Alder
cycloaddition-based metal-free conjugation chemistry was uti-
lized for the synthesis of dendron–polymer conjugates. Novel
TABLE 1 Synthesis Details and Characterization Data of Dendron–Polymer Conjugates
GPCb
Mn, theo
Entry
Polymer
PEGa
Dendrona
Yield (%)
Mn (g/mol)
Mw/Mn
(g/mol)
1
2
3
4
5
6
P1
P2
P3
P4
P5
P6
7
7
7
9
9
9
2 (G1)
3 (G2)
4 (G3)
2 (G1)
3 (G2)
4 (G3)
84
79
77
96
83
84
3160
3440
3600
3660
4320
4980
1.1
1.1
1.3
1.2
1.1
1.3
2560
2800
3260
3120
3590
4520
a
[MI-PEG]0:[Dendron] 5 1:1.05 (P1–P3), 1:2.10 (P4–P6).
b
Calibration with PS as standards. THF is the eluting solvent.
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SCHEME 6 Alkyne-functionalized (P7) and thioglycerol-conjugated (P8) G2-PEG-G2 triblock copolymers.
13 K. Maruyama, Adv. Drug Deliv. Rev. 2011, 63, 161–169.
dendrons provides a simple methodology to obtain multiva-
lent linear PEG polymers. The multiple hydroxyl groups of
these dendron–polymer conjugates could be easily decorated
by alkyne groups to attach desired molecules via [3 1 2]
Huisgen type or thiol–yne “click” reactions.61–68
14 S. M. Ryan, G. Mantovani, X. Wang, D. M. Haddleton. D. J.
Brayden, Expert Opin. Drug Deliv. 2008, 5, 371–383.
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The authors thank the Scientific and Technological Research
Council of Turkey (TUBITAK, Research Grant 109T493) and
State Planning Organization of Turkey (Grant No. DPT
09K120520). A. Sanyal and R. Sanyal thank the Turkish Acad-
emy of Sciences for TUBA-GEBIP fellowship.
18 F. M. Veronese, Biomaterials 2001, 22, 405–417.
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