Degradable dendrimers divergently synthesized via click chemistry

Article abstract of DOI:10.1039/b818183g

Large degradable dendrimers (MW > 30 kDA) were synthesized in a divergent manner utilizing a novel 1,3,5-triazaadamantane (TAA) monomer that can degrade under acidic conditions. The Royal Society of Chemistry.

Full text of DOI:10.1039/b818183g

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Degradable dendrimers divergently synthesized via click chemistryw
Richie E. Kohman and Steven C. Zimmerman*
Received (in Cambridge, UK) 15th October 2008, Accepted 9th December 2008
First published as an Advance Article on the web 13th January 2009
DOI: 10.1039/b818183g
Large degradable dendrimers (MW 4 30 kDA) were synthe-
sized in a divergent manner utilizing a novel 1,3,5-triazaada-
mantane (TAA) monomer that can degrade under acidic
conditions.
The considerable impact of dendrimers on the field of nano-
Fig. 1 Substituted TAA formation and degradation.
technology can be traced to their easily tailored synthesis with
predictable size, shape, and functionality.1 Dendrimers have
been used to prepare organic nanoparticles2 and nanotubes,3
as well as being used for molecular printboards4 and drug
delivery vehicles.5 Recent interest has focused on dendrimers
that degrade in a controlled fashion,6 particularly via hydro-
lysis with an eye toward biological applications.5b Many
hydrolytically labile dendrimers are known,7 but to our knowl-
edge none that have at each branch point a degradable unit
with tunable hydrolysis kinetics. Herein, we report a facile
method to prepare dendrimers containing a degradable 1,3,5-
triazaadamantane (TAA) at each branch point.
We recently introduced the TAA unit as a stable aminal that
undergoes pH dependent hydrolysis to give tris(amino-methyl)-
ethane and substituted benzaldehydes used for its synthesis
(Fig. 1).8 Contrary to many other degradable materials such as
polyesters, TAAs are stable under basic conditions but hydro-
lyze rapidly under acidic conditions to give basic by-products.
Similar to substituted acetals9 and N-ethoxybenzylimida-
zoles,10 alteration of the aromatic ring substitution pattern
affects the rate of TAA degradation.
Recent methods of dendrimer synthesis have enabled the
rapid construction of macromolecules with an increased
amount of structural complexity.11 The copper catalyzed
cycloaddition of azides with alkynes (CuAAC)12 popularized
as ‘‘click chemistry’’ has become widely used as a result of its
Scheme 1 Synthesis of TAA monomer 5.
functional group tolerance, high conversion rate, and mild
reaction conditions. Using an iterative, divergent approach,13a
during the course of the reaction.16 The half life of this
we synthesized dendrimers comprising degradable monomer 5
monomer is expected to be comparable to the previously
reported analog containing an ester substituent.8
with this method.
Synthesis of monomer 5 began by propargylation of TAA
114 followed by acid hydrolysis to afford the desired tris amine
salt 2 (Scheme 1). Benzaldehyde 4 was synthesized by activa-
tion of 315 using DCC–NHS followed by amide formation
with 2-(2-chloroethoxy)ethylamine hydrochloride (ESIw) and
acetal hydrolysis. Condensation of 2 with 4 produced the
desired triazaadamantane in multigram quantities with no
evidence of side reaction between the amino and chloro groups
Dendrimer synthesis began by reacting three equivalents of
monomer with tri-azide core 6 (ESIw) (Scheme 2). Because of
the high solubility of monomer 5 in dichloromethane, the
procedure reported by Lee et al.was used and was found to be
highly effective.17 Azide displacement of terminal chloro
groups produced azide-terminated dendrimer 8. This process
was repeated to produce second and third generation dendri-
mers 9–11. Because of the high molecular weight of monomer
5 (MW = 884) and overall high reaction yields, large
dendrimers can be synthesized rapidly in this fashion.
Department of Chemistry, University of Illinois at Urbana-
Champaign, 600 S. Mathews Avenue, IL, Urbana, 61801, USA.
E-mail: sczimmer@illinois.edu; Fax: +1 217 244 9919
w Electronic supplementary information (ESI) available: Synthetic
procedures and characterization. See DOI: 10.1039/b818183g
Table 1 summarizes the characterization data. Dendrimers
were characterized by IR spectroscopy, MALDI-TOF MS,
and analytical GPC. NMR was not useful because multiple
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Scheme 2 Dendrimer synthesis: (a) 5, CuSO4, NaAsc, CH2Cl2–H2O; (b) NaN3, DMF, 100 1C (see Table 1 for yields).
Table 1 Characterization data for dendrimers 7–11
Compound
Generation
Periphery
TAAs
Yield (%)
GPC PDI
Theoretical mass/g molÀ1
MALDI mass/g molÀ1
7
8
9
10
11
1
1
2
2
3
9 (–Cl)
3
3
12
12
39
86
93
93
96
56
1.01
1.02
1.04
1.06
1.38
3207.2
3266.5
11224.3
11402.4
35279.6
3208.4
3266.4
11227.4
11407.2
35279.1
9 (–N3)
27 (–Cl)
27 (–N3)
81 (–Cl)
diastereomers16 led to broad, uninformative spectra. IR
spectroscopy conveniently monitored the presence and
absence of the azide stretch band at ca. 2100 cmÀ1 (Fig. 2a).
This peak completely disappeared after reaction with mono-
mer 5 for each generation. MALDI-TOF MS confirmed
product by showing mass peaks in good agreement with the
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because TAAs are stable under physiological conditions and
labile under relevant acidic conditions such as those found
in endosomal compartments, tumor tissues, and sites of
inflammation.18
Notes and references
´
1 (a) J. M. J. Frechet and D. A. Tomalia, Dendrimers and Other
Dendritic Polymers, Wiley, New York, 2002; (b) G. R. Newkome,
C. N. Moorefield and F. Vogtle, Dendrimers and Dendrons: Con-
¨
cepts, Syntheses, Applications, VCH, Weinheim, 2001.
2 S. C. Zimmerman, J. R. Quinn, E. Burakowska and R. Haag,
Angew. Chem., Int. Ed., 2007, 46, 8164.
3 Y. Kim, M. F. Mayer and S. C. Zimmerman, Angew. Chem., Int.
Ed., 2003, 42, 1121.
4 M. J. W. Ludden, D. N. Reinhoudt and J. Huskens, Chem. Soc.
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5 (a) A. K. Patri, J. F. Kukowska-Latallo and J. R. Baker, Jr, Adv.
Drug Delivery Rev., 2005, 57, 2203; (b) C. C. Lee, J. A. MacKay, J.
M. J. Frechet and F. C. Szoka, Nat. Biotechnol., 2005, 23, 1517.
´
Fig. 2 (a) Azide region of IR spectra of core and dendrimers;
(b) GPC traces of monomer and dendrimers.
6 M. Gingras, J.-M. Raimundo and Y. M. Chabre, Angew. Chem.,
Int. Ed., 2007, 46, 1010.
7 (a) H. Ihre, O. L. Padilla de Jesu´ s and J. M. J. Frechet, J. Am.
´
Chem. Soc., 2001, 123, 5908; (b) M. W. Grinstaff, Chem.–Eur. J.,
2002, 8, 2838; (c) N. G. Lemcoff and B. Fuchs, Org. Lett., 2002, 4,
731. Self-immolative dendrimers also degrade at each branch
point; (d) M. L. Szalai, R. M. Kevwitch and D. V. McGrath,
J. Am. Chem. Soc., 2003, 125, 15688; (e) F. M. H. de Groot,
C. Albrecht, R. Koekkoek, P. H. Beusker and H. W. Scheeren,
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calculated values (ESIw). Analytical GPC showed narrow,
symmetric peaks characteristic of perfect dendrimers
(Fig. 2b). The characterization showed complete conversion
of all reactions for the first two dendrimer generations.
Imperfections resulting from incomplete conversion, which
are a common occurrence when synthesizing dendrimers
divergently, were only seen in product 11 in which 27 reactions
per molecule were needed. Only the trace for dendrimer 11
shows evidence of incomplete monomer attachment as
evidenced by a shoulder at higher retention times.
´
9 E. R. Gilles and J. M. J. Frechet, Bioconjugate Chem., 2005, 16,
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10 S. D. Kong, A. Luong, G. Manorek, S. B. Howell and J. Yang,
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Addition of HCl to
a solution of compound 9 in
11 Notable examples: (a) T. Kawaguchi, K. L. Walker, C. L. Wilkins
and J. S. Moore, J. Am. Chem. Soc., 1995, 117, 2159; (b) F. Zeng
and S. C. Zimmerman, J. Am. Chem. Soc., 1996, 118, 5326. For a
THF–MeOH confirmed that the dendrimers were fully
degradable. The by-products, which were analyzed by 1H
NMR and mass spectrometry, corresponded to the aldehyde
groups from the periphery of the dendrimer, the aldehyde
groups from the interior of the dendrimer, and the core.
Amounts and ratios of compounds were in good agreement
with the calculated values (ESIw).
In conclusion, dendrimers were synthesized from a degrad-
able 1,3,5-triazaadamantane (TAA) monomer. The largest
contains 39 TAA molecules, displays 81 functional groups
on its periphery, and has a molecular weight above 35 kDa.
Although a divergent strategy was used, a remarkably high
conversion was observed for several generations. The method
demonstrated here allows the synthesis of dendrimers that
contain TAA groups throughout the entire structure. Because
an iterative strategy is used, it should be possible to incorpo-
rate TAA monomers with different degradation rates thus
allowing for the creation of generation dependent degradable
dendrimers possessing both spatial and temporal control of
degradation. After appropriate surface modification that
would enable water solubility, these materials may be useful
for biological applications such as drug and/or gene delivery
more recent orthogonal approach see: (c) P. Antoni, D. Nystrom,
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C. J. Hawker, A. Hult and M. Malkoch, Chem. Commun., 2007,
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12 V. V. Rostovtsev, L. G. Green, V. V. Fokin and K. B. Sharpless,
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13 Selected examples of dendrimer synthesis via CuAAC:
(a) M. J. Joralemon, R. K. O’Reilly, J. B. Matson,
A. K. Nugent, C. J. Hawker and K. L. Wooley, Macromolecules,
2005, 38, 5436; (b) G. Franc and A. Kakkar, Chem. Commun.,
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S.-H. Jin, J. Polym. Sci., Part A: Polym. Chem., 2008, 46, 1083;
(d) S. L. Elmer, S. Man and S. C. Zimmerman, Eur. J. Org. Chem.,
2008, 3845.
14 T. J. Dunn, W. L. Neumann, M. M. Rogic and S. R. Woulfe,
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15 S. L. Roberts, R. L. E. Furlan, S. Otto and J. K. M. Sanders, Org.
Biomol. Chem., 2003, 1, 1625.
16 Consistent with ref. 8, compound 5 is produced as a mixture of
diastereomers in which 90% is in the conformation drawn. This
mixture had no effect on the dendrimer synthesis.
17 B.-Y. Lee, S. R. Park, H. B. Jeon and K. S. Kim, Tetrahedron
Lett., 2006, 47, 5105.
18 (a) I. Mellman, R. Fuchs and A. Helenius, Annu. Rev. Biochem.,
1986, 55, 663; (b) I. F. Tannock and D. Rotin, Cancer Res., 1989,
49, 4373.
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This journal is The Royal Society of Chemistry 2009
796 | Chem. Commun., 2009, 794–796