Efficient synthesis of water-soluble, phosphonate-terminated polyester dendrimers

Article abstract of DOI:10.1016/j.tetlet.2015.11.035

Simple and effective syntheses of novel, water-soluble, phosphonate-terminated polyester dendrimers varying in size and structure are described. These macromolecular compounds, consisting of thiophosphoric and 1,3,5-benzenetricarboxylic ester building blocks may find potential applications in health sciences as microbicides and/or as useful macromolecular models for functional coatings of superparamagnetic iron oxides (SPIOs) nanoparticles intended for use in hyperthermal therapy and magnetic resonance imaging (MRI). The dendrimers, possessing free phosphonate functional groups on the surface, were prepared in high yields from previously synthesized phosphorus-based substrates with 3,5-bis(dimethoxyphosphonyl)-methyl]benzoic acid (4), being an essential precursor of the dendrimer polyanionic surface. In addition, an interesting example of virtual coupling between remote nuclei in the ¹³C NMR spectrum of bisphosphonate monomer 3 was observed.

Full text of DOI:10.1016/j.tetlet.2015.11.035

Tetrahedron Letters xxx (2015) xxx–xxx
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Efficient synthesis of water-soluble, phosphonate-terminated
polyester dendrimers
⇑
´
Grzegorz M. Salamonczyk
´
Centre of Molecular and Macromolecular Studies, The Polish Academy of Sciences, Sienkiewicza 112, 90-363 Łódz, Poland
a r t i c l e i n f o
a b s t r a c t
Article history:
Simple and effective syntheses of novel, water-soluble, phosphonate-terminated polyester dendrimers
varying in size and structure are described. These macromolecular compounds, consisting of
thiophosphoric and 1,3,5-benzenetricarboxylic ester building blocks may find potential applications in
health sciences as microbicides and/or as useful macromolecular models for functional coatings of super-
paramagnetic iron oxides (SPIOs) nanoparticles intended for use in hyperthermal therapy and magnetic
resonance imaging (MRI). The dendrimers, possessing free phosphonate functional groups on the surface,
were prepared in high yields from previously synthesized phosphorus-based substrates with 3,5-bis
(dimethoxyphosphonyl)-methyl]benzoic acid (4), being an essential precursor of the dendrimer
polyanionic surface. In addition, an interesting example of virtual coupling between remote nuclei in
the 13C NMR spectrum of bisphosphonate monomer 3 was observed.
Received 7 October 2015
Revised 30 October 2015
Accepted 10 November 2015
Available online xxxx
Keywords:
Dendrimer
Polyester
Phosphonate
Virtual coupling
1,3,5-Benzenetricarboxylate
Ó 2015 Elsevier Ltd. All rights reserved.
Dendrimers1 have created a remarkable interest in areas rang-
ing from materials science to biomedical applications. These
macromolecules exhibit a high density of surface functional groups
that can be easily tuned according to the field of application.
Charged dendrimers are generally water-soluble compounds use-
ful for biomedical applications, and polyanionic dendrimers are
proven to be less toxic than polycationic ones.2 Probably, the most
important feature of polyanionic dendrimers is their significant
antiviral activity, so they may serve as microbicidal drugs in their
own right.3 Antiviral dendrimers acting as non-natural imitations
of the target cell surface are commonly designed with anionic sur-
face groups. The polyanionic dendritic drug then competes with
the cellular surface for virus binding, resulting in a lower cell-virus
infection rate. On this matter, several dendrimeric frameworks ter-
minated with carboxylic4 and sulfonic3a acid functional groups,
and to a lesser extent dendrimers,5 and dendrons6 capped with
phosphonic and amino phosphonic7 acids residues have been syn-
thesized. But, none of these were polyester compounds. Interest-
ingly, the ‘smallest’ dendrimer (generation one) terminated with
amino phosphonic acid residues showed the most activity (com-
pared with similar but higher generation structures), for example,
multiplication of human natural killer cells.8 These and other bio-
logical properties of organophosphorus dendrimers have been
recently summarized comprehensively.9
However, phosphonic acids possess very strong binding affinity
to the metal oxide surfaces. Consequently, this phenomenon
sparked various studies and decorated magnetic metal oxide
nanoparticles (NPs) with phosphonate terminated organic com-
pounds have been synthesized.10 Several research groups work
on applications of superparamagnetic iron oxide (SPIO) NPs,
including both diagnostics (MRI) and therapy (hyperthermic
destroying of tumors). To make metal oxide NPs biologically toler-
able,11 suitable surface modifications applying compounds having
free phosphonate groups as anchors are necessary.12 Recently,
the synthesis of small-sized phosphonated dendrons as potential
organic coatings for iron oxide nanoparticles has been disclosed.13
On the other hand, polyphosphonate dendrimers, monodis-
persed entities whose relevant characteristics (size, hydrophilicity
etc.) and polyfunctionality can be tuned as a function of their gen-
eration, should display much stronger binding to iron oxide NPs
than monophosphonate or bisphosphonate dendrons.13 Among
dendrimers, polyesters have proved to be particularly important,14
because they have biodegradability potential, and in the presence
of enzymes can be hydrolyzed into small molecules, which are able
to leave the body.
Recently, we developed a method for the synthesis of den-
drimeric polyphosphates and their analogs.15 We also have
reported, the effective syntheses of new polyester dendrimers
based on a trimesic acid framework derivative.4b,16 In a continua-
tion of these efforts, the straightforward and efficient syntheses
of new, water-soluble, phosphonate terminated, polyanionic
⇑
Tel.: +48 42 680 3217; fax: +48 42 680 3261.
E-mail address: gmsalamo@cbmm.lodz.pl
http://dx.doi.org/10.1016/j.tetlet.2015.11.035
0040-4039/Ó 2015 Elsevier Ltd. All rights reserved.
´
Please cite this article in press as: Salamonczyk, G. M. Tetrahedron Lett. (2015), http://dx.doi.org/10.1016/j.tetlet.2015.11.035

´
G. M. Salamonczyk / Tetrahedron Letters xxx (2015) xxx–xxx
2
S
dendrimers composed of both thiophosphate and 1,3,5-benzenet-
ricarboxylate units are reported herein.
S
P
P
O
O
O
OH
2
3
Although the surface unit precursor, 3,5-bis[(dimethoxyphos-
phonyl)methyl]benzoic acid (4) is a known compound,17 its syn-
thesis required slight improvements. The synthesis commenced
from a convenient starting material, methyl 3,5-bis(hydroxyl-
methyl)benzoate (1), which can be easily obtained from the parent
trimesic acid.16
8
EDC
DMAP
4
88%
CH2P(O)(OR)2
S
S
P
P
Bromination of diol 1 with phosphorus tribromide18 in carbon
CH2P(O)(OR)2
O
O
O
O
2
3
O
tetrachloride provided dibromide
2 in 90% isolated yield.
9: R=Me
10: R=H
(Scheme 1) An Arbusov19 reaction (90 °C, overnight) using an
excess of trimethyl phosphite (neat) afforded the corresponding
bisphosphonate 3 in high yield (84%). It is worth noting that bis-
phosphonate 3 cannot be obtained directly from diol 1 using recent
methodology,20 which does not work in the case of methyl phos-
phonates. The carboxylic ester functionality in bisphosphonate 3
was hydrolyzed using aqueous lithium hydroxide (1 M) to provide
the key monomer, 3,5-bis[(dimethoxyphosphonyl)methyl]benzoic
acid (4) in 86% yield. This compound represents an AB2-type mono-
mer. The A group (carboxyl) is active and the B groups (phospho-
nate) are protected such that the A group solely reacts with the B
(active) groups in the prior generation of the dendrimer. Another
monomer, this time, A2B, 7 (in concordance to the above descrip-
tion) was obtained from trimesic acid dimethyl ester (5).18,21 In
this case the free carboxylic acid of compound 5 was reacted with
di-tert-butyl-dicarbonate to yield the corresponding trimesic acid
tert-butyl-dimethyl ester (89%).22 Selective hydrolysis of both
methyl groups in the triester was effectively achieved using aque-
ous lithium hydroxide to provide compound 6 in high yield (88%).
Another highly chemoselective reaction was the reduction of the
two carboxylate groups in diacid monoester 6 using borane-
dimethyl sulfide complex, which furnished 3,5-bis(hydrox-
ymethyl)benzoic acid tert-butyl ester (7) in a high isolated yield
(83%).
TMSBr/MeOH
Scheme 2. Synthesis of dendrimer 10 with 12 phosphonate groups.
corresponding trimethylsilyl phosphonate ester intermediate that
was swiftly hydrolyzed in situ to give phosphonic acids 10 in a pro-
tic solvent (MeOH). All of the deprotection stages were unambigu-
ously evidenced by 31P {1H} NMR. The presence of subsequent
intermediates, bis-trimethylsilyl phosphonate esters (8 ppm) and
even very unstable phosphonic acids trimethylsilyl esters
(ꢀ17 ppm, broad singlet, most likely due to the existence of the
P-epimeric isomers) were detected. These rather mild conditions
did not cause cleavage of the other ester bonds present in the
macromolecule and the integrity of the dendritic structure was
preserved. Dodecaphosphonic acid 10 was further transformed
into its dodecaanion (sodium hydrogen phosphonates) using aque-
ous sodium bicarbonate.
To demonstrate the usefulness of the presented synthetic
approach, another, much larger phosphonate polyester dendrimer
13, (theoretical mol. wt. 12096 D) was synthesized from den-
drimeric substrate 11.4b During this synthesis, the fully protected
intermediate 12 was isolated, which was used to form novel
polyanionic compound 13 (Fig. 1). Despite the fact that dendrimer
13 (generation four, the largest unprotected compound described
here, overall yield 50%, from 11) was composed of a lipophilic, thio-
phosphate-based interior (22 P = S functions), possessing 24 4-car-
bon chains, 21 3-carbon chains, and 24 aromatic rings, the effect of
the surface polar phosphonate groups seemed to predominate.
Free acid 13 was sparingly soluble in water, and in order to achieve
reasonable solubility (50 mg/1 mL), it was necessary to convert a
few (statistically three/four) of the 48 P(O)(OH)2 groups into the
corresponding sodium salts.
The phosphorus-based dendrimers, used in this project as sub-
strates were synthesized in a divergent manner from readily avail-
able, inexpensive chemicals, via an amidophosphite method. The
detailed syntheses of thiophosphate dendrimers 8 and 11 have
been described previously.4b,15 It is worth noting that thiophos-
phate dendrimers turned out to be well tolerated by biological sys-
tems.23 Hydroxy-terminated, first generation, thiophosphate
dendrimer 8 was reacted with an excess of acid 4, (Scheme 2) in
the presence of the water-soluble carbodiimide, 1-ethyl-3-(3-
dimethylaminopropyl)carbodiimide24 (EDC), and 4-dimethy-
laminopyridine (DMAP) to afford the second generation dendrimer
9 in 88% isolated yield. Cleavage of the terminal methyl phospho-
The presented methodology also enabled the convergent syn-
thesis of phosphonate-capped polyester dendrimers. Moreover,
depending on the nature of the substituents connected to both
sides of the starting monomer or focal point, the interior of the
macromolecule can be tuned accordingly. The synthesis of the
nate esters in
method,25 by means of a large excess of trimethylsilyl bromide
(TMSBr) which transformed methyl phosphonate into the
9 was accomplished by applying, McKenna’s
9
O
O
HOH2C
MeOOC
CH2OH
BrH2C
CH2Br
(MeO)2PH2C
CH2P(OMe)2
a
90%
b
84%
COOMe
COOMe
COOR
3
4
: R=Me
c
86%
1
2
: R=H
HOOC
COOH
HOH2C
CH2OH
COOMe
d then c
78%
e
83%
COOH
COOtBu
COOtBu
5
7
6
Scheme 1. Reagents and conditions: (a) PBr3, CCl4, rt; (b) P(OMe)3, 90 °C; (c) LiOH aq, MeOH, 4 °C; (d) di-tert-butyl-dicarbonate, DMAP, CH2Cl2, rt; (e) B2H6Á(CH3)2S, THF, rt.
´
Please cite this article in press as: Salamonczyk, G. M. Tetrahedron Lett. (2015), http://dx.doi.org/10.1016/j.tetlet.2015.11.035

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3
G. M. Salamonczyk / Tetrahedron Letters xxx (2015) xxx–xxx
OR
first generation dendron 14 in 93% isolated yield (Scheme 3). The
terminal tert-butyl protecting group was removed from 14, (95%
yield) using trifluoroacetic acid in the presence of anisole and the
resulting acid 15 was used without further purification. A three-
fold molar excess of dendron 15 was then condensed with triol
164b,15a in the presence of EDC and DMAP to afford the second gen-
eration protected dendrimer 17 in 88% yield. In the end, all methyl
groups of the terminal phosphonates were quantitatively removed
by applying the Me3SiBr/MeOH cleavage conditions, as described
for previous compounds. The final dendrimer 18 turned out to be
quite soluble in water (more than 50 mg/1 mL) even at the stage
of the free acids. Both the fully protected dendrimers 10, 12, 17
(colorless) and corresponding final dendrimeric acids 11, 13, 18
(pale yellow) were stable viscous oils, whereas conversion of at
least 10% of the acidic groups into their sodium salts resulted in
the formation of white nonhygroscopic solids. The structures and
high purity of all the dendrimeric products were confirmed by
NMR spectroscopy and MALDI TOF mass spectrometry (see ESI).
In conclusion, using simple and readily available monomers, a
highly efficient method for the synthesis of novel water-soluble
phosphonate dendrimers with potential applications in biomedical
sciences was presented. These applications may include the use of
phosphonate polyanionic dendrimers as antiviral compounds in
their own right, and as macromolecular models (free acids) for
functional coatings of superparamagnetic iron oxides (SPIOs)
nanoparticles intended for medical diagnosis (MRI) and therapy
(hyperthermia). Even the tetraphosphonate dendron, 15 (after
esterification with a long chain alcohol or polyethylene glycol
(PEG)) seems to be an interesting precursor of the anchor for SPIO
NPs coating. The mild conditions of both the coupling and depro-
tection reactions provided highly pure and water-soluble macro-
molecular materials in good overall yields. This approach could
be made more general to enable the conversion of virtually any
polyfunctional compound terminated with N nucleophilic func-
tions (e.g., hydroxy, thiol, or amino), into its 2N polyphosphonate
derivative.
OR
OR
OR
OR
S
O
O
O
O
P
RO
O
P
O
P
O
OR
OR
O
S
S
O
O
P
O
O
O
P
O
O
P
O
O
P
S
RO
OR
OR
S
O
O
S
O
O
O
S
O P
O
S
OR
S
O
O
S
P
O
O
P
S
O
O
O
O
O
O
S
O
O
P
O
O
P
O
P
O
O P
S
OR
S
O
O
P
RO
O
S
S
S
O
O
O
OR
RO
P
O
O
P
O
O
O
P
O
S
O
O
P
O
O
S
O
P
S
OR
RO
S
O
O
O
O
O
O
P
OR
P
O
S
RO
O
RO
RO
RO
P(O)(OMe)2
13: R=
(HO)2(O)P
OR
P(O)(OH)2
O
O
11: R=H; 12: R=
(MeO)2(O)P
Figure 1. Structures of dendrimeric substrate 11; fully protected intermediate
dendrimer 12, and polyacid dendrimer 13.
2nd generation polyester phosphonate-terminated dendrimer
commenced from the A2B monomer 7. Diol 7 was condensed with
an excess of acid 4, in the presence EDC and DMAP to provide the
HO
O
O
OH
O
S
R1
R1
P
O
R1
HOH2C
CH2OH
16
0.33 equiv.
acid 4 (2.1 equiv.)
HO
O
R1
a 93%
c 88%
O
COOtBu
O
7
R1
R1
COOR
R1
O
1
14:
15:
R=tert-butyl, R =CH P(O)(OMe)2
2
b
O
O
1
O
R=H, R =CH2P(O)(OMe)2
R1
R1
O
P
R1
O
O
O
O
O
O
O
O
O
S
O
O
R1
R1
O
O
R1
O
R1
O
O
1
17:
18:
R =CH2P(O)(OMe)2
R1
d
1
R =CH2P(O)(OH)2
R1
Scheme 3. Reagents and conditions: (a) EDC, DMAP, CH2Cl2, rt; (b) CF3COOH, anisole, CH2Cl2, rt; (c) EDC, DMAP, CH2Cl2, rt; (d) Me3SiBr, CH2Cl2, MeOH, rt.
´
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G. M. Salamonczyk / Tetrahedron Letters xxx (2015) xxx–xxx
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This work was supported in part by the Ministry of Science and
Higher Education, Grant No. N N204 030836.
Supplementary data
Supplementary data (detailed synthetic procedures and analy-
ses of compounds 6, 7, 9, 10, 12, 13, 14, 15, 17, 18, as well as some
additional and important NMR spectra (Figure I, II, III and IV)) asso-
ciated with this article can be found, in the online version, at
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´
Please cite this article in press as: Salamonczyk, G. M. Tetrahedron Lett. (2015), http://dx.doi.org/10.1016/j.tetlet.2015.11.035