J. Am. Chem. Soc. 2001, 123, 2905-2906
2905
and materials are needed to address this present limitation.
“Biodendrimers” are a new class of dendritic polymers. These
dendrimers are comprised of building blocks known to be
biocompatible or degradable to natural metabolites in vivo. Herein,
we report the divergent synthesis and characterization of novel
dendrimers composed of glycerol and lactic acid.
Synthesis and Characterization of Polyether-Ester
Dendrimers from Glycerol and Lactic Acid
Michael A. Carnahan and Mark W. Grinstaff*
Departments of Chemistry and Ophthalmology
Paul M. Gross Chemical Laboratory, Duke UniVersity
Durham North Carolina 27708
Linear polymers of lactic acid and other such polymers (e.g.,
poly(glycolic acid), poly(ꢀ-caprolactone), poly(ethylene glycol),
and poly(trimethylene carbonate)) constitute a class of materials
well suited for research and clinical applications ranging from
drug delivery to tissue engineering.33-38 Specifically, poly(lactic
acid) (PLA) and its closely related analogue poly(glycolic acid)
(PGA) are polyesters of naturally occurring hydroxy acids, and
are used for biomedical applications since these polymers possess
favorable biocompatibility and mechanical strength.39,40 First used
as bioresorbable surgical sutures,41 these polymers are also widely
investigated for applications in orthopedics (e.g., screws, pins,
scaffolds), wound closure (e.g., staples, dressings, meshes), and
drug delivery (e.g., microspheres, hollow fibers). Incorporation
of similar biocompatible monomers in dendrimers represents a
new means to create well-defined polymeric structures for
biomedical and tissue engineering applications.
Scheme 1 shows a divergent strategy to synthesize a third
generation [G3] poly(glycerol-lactic acid) dendrimer, [G3]-
PGLLA. First, a tetrafunctional core is produced in three steps.
cis-1,3-O-Benzylideneglycerol, 1, is treated with NaH followed
by the addition of 2-bromopropionic acid to afford 2-[(cis-1,3-
O-benzylideneglycerol)-2-propionic acid], 2, which is easily
purified by recrystallization in cold (-20 °C) ethyl ether (77%
yield). Compounds 1 and 2 are next coupled in the presence of
1.5 equiv of N,N-dicyclohexylcarbodiimide (DCC) and 0.5 equiv
of 4-(dimethylamino)pyridinium 4-toluenesulfonate (DPTS)42 to
afford the key protected tetrahydroxy-core in 94% yield. The
protected [G0]-PGLLA core is easily separated from the remain-
ing carboxylic acid starting material by column chromatography.
The core is subsequently deprotected by hydrogenolysis (10%
(w/w) of 10% Pd/C; 50 psi of H2) in ethyl acetate/MeOH (3:1)
to yield the G0 dendrimer, 3 ([G0]-PGLLA-OH; 94% yield).
Next, 4 equiv of 2 are coupled to [G0]-PGLLA-OH in the
presence of 6 equiv of DCC and 2 equiv of DPTS to produce
[G1]-PGLLA-bzld, 4, in 88% yield. Again, column chromatog-
raphy is used to isolate 4 and residual DCC is removed by
precipitation of 4 in cold ethyl ether. Subsequent hydrogenolysis
in THF affords [G1]-PGLLA-OH, 5 (94% yield). The [G2]-
PGLLA-bzld, 6, dendrimer is prepared by reacting 8 equiv of 2
with [G1]-PGLLA-OH in the presence of 10 equiv of DCC and
4 equiv of DPTS (77% yield). Hydrogenolysis of 6 affords the
G2 dendrimer, [G2]-PGLLA-OH, 7 (88% yield). Reiteration of
ReceiVed October 24, 2000
Dendrimers are globular monodisperse polymers composed of
branched repeating units emitting from a central core.1-8 These
macromolecules are synthesized using either a divergent (from
core to surface)9-12 or a convergent (from surface to core)13
approach. Since the reports by Tomalia and Newkome, this
research area has undergone tremendous growth in the past
decade.1-8,13-16 Compared to linear polymers, dendrimers possess
high surface area-to-volume ratios, exhibit numerous end groups
for functionalization, and have small polydispersity indices (PDI)
with well-defined interior and exterior regions. These character-
istics translate to unique properties such as low viscosity, high
solubility and miscibility, and adhesiveness;1-8 consequently,
dendrimers are of interest for a wide range of industrial and
medical applications. Dendrimers currently available and inves-
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are limited to derivatives of aromatic polyethers, aliphatic
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10.1021/ja005726+ CCC: $20.00 © 2001 American Chemical Society
Published on Web 03/03/2001