Convergent synthesis of internally branched PAMAM dendrimers

Article abstract of DOI:10.1021/ol050040d

(Chemical Equation Presented) A series of aliphatic internally branched poly(amido amine) dendrons and dendrimers has been synthesized. The internal branching unit was 1,2-propanediamine and a series of PAMAM-type dendrons of the types AB₂, AB₄, and AB₈ were built. These were anchored on a core molecule containing four carboxylic acid moieties and the 1,2-propanediamine unit resulted in PAMAM dendrimers with 4, 8, 16, and 32 end groups.

Full text of DOI:10.1021/ol050040d

ORGANIC
LETTERS
2005
Vol. 7, No. 7
1295-1298
Convergent Synthesis of Internally
Branched PAMAM Dendrimers
Michael Pittelkow and Jørn B. Christensen*
Department of Chemistry, UniVersity of Copenhagen,
UniVersitetsparken 5, DK-2100, Denmark
jbc@kiku.dk
Received January 10, 2005
ABSTRACT
A series of aliphatic internally branched poly(amido amine) dendrons and dendrimers has been synthesized. The internal branching unit was
1,2-propanediamine and a series of PAMAM-type dendrons of the types AB2, AB4, and AB8 were built. These were anchored on a core molecule
containing four carboxylic acid moieties and the 1,2-propanediamine unit resulted in PAMAM dendrimers with 4, 8, 16, and 32 end groups.
Future applications of dendrimers rely on efficient and prac-
tical synthetic procedures. Since the synthesis of the first
dendrimers by Vo¨gtle and co-workers in 19781 much effort
has been put into the synthesis and applications of these
aesthetically beautiful macromolecules. Catalysis, drug-de-
livery systems, molecular encapsulation, molecular light-
harvesting, guest-host chemistry, artificial antibodies, and
many other exciting applications have been suggested and
demonstrated.2
The early synthetic efforts in dendrimer synthesis applied
the divergent synthesis procedure building the dendrimers
from the core by an iterative synthetic procedure. Both major
commercially available dendrimers, the poly(propylene
amine) dendrimer3 and the poly(amido amine) dendrimer,4
were constructed by this procedure. Other types of dendrim-
ers such as Majoral’s phosphorus containing dendrimers,5
Newcome’s polyamide dendrimers,6 and Denkewalter’s poly-
lysine dendrimers7 were products of the divergent approach.
The convergent approach to dendrimer synthesis intro-
duced by Frechet and co-workers revolutionized the synthetic
approaches to monodisperse dendrimers.8 Following Fre´-
chet’s poly(aryl ether) dendrons many other types of den-
drons and dendrimers have been synthesized using both
classical solution phase synthesis and solid-phase synthesis.9
Building dendrimers via the convergent approach allows for
the synthesis of nonsymmetrical dendrimers10,11 and for
specific incorporation of function into the dendrimer inter-
ior.12
(3) (a) de Brabander-van den Berg, E. M. M.; Meijer, E. W. Angew.
Chem., Int. Ed. Engl. 1993, 32, 1308. (b) Wo¨rner, C.; Mu¨lhaupt, R. Angew.
Chem., Int. Ed. Engl. 1993, 32, 1306.
(4) Tomalia, D. A.; Barker, H.; Dewald, J.; Hall, M.; Kallos, G.; Martin,
S.; Roeck, J.; Ryder, J.; Smith, P. Polym. J. 1985, 17, 117.
(5) (a) Launay, N.; Caminade, A. M.; Majoral, J. P. J. Am. Chem. Soc.
1995, 117, 3282. (b) Galliot, C.; Pre´vote´, D.; Caminade, A. M.; Majoral, J.
P. J. Am. Chem. Soc. 1995, 117, 5470.
(6) Newcome, G. R.; Yao, Z.; Baker, G. R.; Gupta, V. K. J. Org. Chem.
1985, 50, 2003.
(7) Denkewalter, R. G., U.S. Patent 4289872, 1981.
(8) Hawker, C. J.; Fre´chet, J. M. J. J. Am. Chem. Soc. 1990, 112, 7638.
(9) Grayson, S. M.; Fre´chet, J. M. J. Chem. ReV. 2001, 101, 3819.
(1) Buhleier, E.; Wehner, W.; Vo¨gtle, F. Synthesis 1978, 2, 155.
(2) (a) Topics in Current Chemistry; Springer-Verlag: Heidelberg; Vols.
197, 210, 212, 217 and 228. (b) Fre´chet, J. M. J.; Tomalia, D. A. Dendrimers
and Other Dendritic Polymers; Wiley Series in Polymer Science; Wiley:
New York, 2001. (c) Bosman, A. W.; Janssen, H. M.; Meijer, E. W. Chem.
ReV. 1999, 99, 1665. (d) Hecht, S.; Fre´chet, J. M. J. Angew. Chem., Int.
Ed. 2001, 40, 74.
10.1021/ol050040d CCC: $30.25
© 2005 American Chemical Society
Published on Web 03/09/2005

Scheme 1
Scheme 3
Scheme 2
The synthesis of all-aliphatic poly(amido amine) dendrim-
ers via the convergent approach has presented a significant
challenge for solution phase synthesis.13 A major challenge
in the synthesis of nonsymmetrical dendrons with solution
phase chemistry is the fact that the use of a large excess of
reagents is often not feasible. In the classical PAMAM
dendrimer synthesis developed by Tomalia and co-workers,
a large excess of both 1,2-ethanediamine and methyl acrylate
aided the reactions in going to completion.
Herein we report a convergent regioselective synthesis of
a series of nonsymmetrical internally branched PAMAM-
type dendrimers using highly effective protection group
chemistry in combination with a very efficient peptide
coupling reagent.
The first step in the dendron synthesis was a selective boc
protection of 1,2-propanediamine on the amino group located
on the primary carbon (Scheme 1). This boc protection
proceeded selectively with tert-butyl phenyl carbonate as the
electrophile in absolute ethanol, and the product was isolated
without the use of column chromatography.14 The boc
protected diamine (1) was then reacted twice with benzyl
acrylate. This reaction was rather sluggish, but performing
the reaction neat in an excess of the Michael acceptor at 75
°C for 7 days yielded the desired product (2) in 90% yield.
This product constitutes the fully orthogonally protected AB2
wedge. The two carboxylic acid moieties are benzyl protected
and the amine is boc protected. The orthogonal deprotection
reactions proceeded smoothly by catalytic hydrogenation with
(10) Kremers, J. A.; Meijer, E. W. J. Org. Chem. 1994, 59, 4262.
(11) Unsymmetrical PAMAM-type dendrimers have been synthesized
by using a divergent/divergent approach: Martin, I. K.; Twyman, L. J.
Tetrahedron Lett. 2001, 42, 1119.
(12) Hecht, S. J. Polym. Sci. Part A: Polym. Chem. 2003, 41, 1047.
(13) Some examples of dendrimers that resemble poly(amido amine)
dendrimers synthesized in a convergent manner include: (a) Kim, Y.; Zeng,
F.; Zimmerman, S. C. Chem. Eur. J. 1999, 5, 2133. (b) Kim, C.; Kim, Y.
T.; Chang, Y. J. Am. Chem. Soc. 2001, 123, 5586. (c) Romagnoli, B.; van
Baal, I.; Price, D. W.; Harwood, L. M.; Hayes, W. Eur. J. Org. Chem.
2004, 4148. (d) Twyman, L. J.; Beezer, E.; Mitchell, J. C. Tetrahedron
Lett. 1994, 4423. (e) Rannard, S.; Davis, N.; McFarland, H. Polym. Int.
2000, 1002. (f) Brouwer, A. J.; Mulders, S. J. E.; Liskamp, R. M. J. Eur.
J. Org. Chem. 2001, 1903. (g) Vinogradov, S. A.; Lo, L.-W.; Wilson, D.
F. Chem. Eur. J. 1999, 5, 1338.
(14) Pittelkow, M.; Lewinsky, R.; Christensen, J. B. Synthesis 2002, 15,
2195.
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Org. Lett., Vol. 7, No. 7, 2005

Scheme 4
Pd/C in ethanol (benzyl groups) and by acidolysis with TFA
in CH2Cl2 (Boc group).15 These transformations are shown
in Scheme 1.
Isolation of the free amine of the boc deprotected wedge
(3) was possible by column chromatography on silica with
some loss of yield. Distillation of this amine was not possible
due to a retro-Michael reaction producing benzyl acrylate.
These results prompted us to design a synthesis of the next
wedges using the fully protected AB2 wedge (2) as the
starting material.
Benzyl acrylate was conveniently synthesized from acrylic
acid and benzyl chloride on a large scale (3 mol) in high
yield by heating the two components in DMF with K2CO3
as the base (Scheme 2). This procedure proved superior to
previously described methods with acrylic chloride and
benzyl alcohol in our hands.
Thus, the AB2 wedge (2) was deprotected with TFA in
CH2Cl2 followed by evaporation of all volatiles. This left
the TFA salt as described above.
In the synthesis of the fully protected AB4 dendron (5)
this salt was converted to the free amine by treatment with
Et3N (in situ) and this was used directly in the coupling
reactions with the two carboxylic acid moieties in compound
4. This reaction sequence is shown in Scheme 3.16
The coupling reagent PyBOP17 was found superior to
DCC,18 TFFH,19 and a number of other commercially
available peptide coupling reagents. An advantage of amide
Figure 1. Structure of the dendrimers 9, 10, and 11 prepared in
80%, 75%, and 51% yield from 8 and the respective dendrons.
(15) Greene, T. W.; Wuts, P. G. M. ProtectiVe Groups in Organic
Chemistry, 3rd ed.; Wiley: New York, 1999.
(16) General procedure for all amide coupling reactions used in this
work: Boc protected amine wedge (1 equiv per carboxylic acid moiety)
was treated with 25% TFA in CH2Cl2 for 16 h at room temperature. The
reaction mixture was evaporated to dryness and dried in vacuo. The resulting
amine salt, PyBOP (1.25 equiv per carboxylic acid moiety), and the
carboxylic acid were suspended in CH2Cl2 and then Et3N (4 equiv per
carboxylic acid) was added at room temperature resulting in a clear solution.
This solution was stirred until the reaction was complete. Aqueous workup
followed by chromatography on silica or biobeads (SX-1) gave the desired
dendrons and dendrimers.
coupling reactions with PyBOP as the coupling reagent was
that preactivation of the carboxylic acid was avoided.
Deprotection of the boc protection group from the fully
protected AB4 wedge (5) followed by amide coupling to
(17) PyBOP: benzotriazole-1-yl-oxy-tris-pyrolidino-phosphinium hexaflu-
orophosphate.
Org. Lett., Vol. 7, No. 7, 2005
1297

resulting tetra ester (7) was transformed into the correspond-
ing tetra acid by hydrogenolysis, using Pd/C as the catalyst.
The synthesis of the core molecule is shown in Scheme 4.
The three PAMAM dendrons (2, 5, and 6) were anchored
to the tetracarboxylic acid core (8) by using the deprotection/
coupling protocol used for the synthesis of the dendrons.
This yielded the series of dendrimers with 8 (9), 16 (10),
and 32 (11) benzyl ester end groups as shown in Figure 1.
The yields of the dendrimers upon anchoring of the
dendrons to the core drop with each generation presumably
due to steric congestion in the vicinity of the core.
The purity of the series of dendrimers was confirmed by
SEC, NMR, and MALDI-MS. The MALDI spectrum of the
dendrimer with 16 end groups (10) and an overlay of the
SEC spectra of the various generations of dendrimers are
shown in Figure 2. The diasteriomeric and enantiomeric
nature of the dendrimers gives rise to relatively broad NMR
spectra. This fact does not, however, interfere with the
purification of the dendrimers by size exclusion chromatog-
raphy.
In conclusion, we have presented a novel convergent
procedure for the solution phase synthesis of a series of
internally branched PAMAM dendrimers.
Acknowledgment. We thank Jeppe Madsen for assistance
with the SEC measurements and Kathrine Petersen and
Solveig K. Hansen for recording the MALDI-MS.
Supporting Information Available: Experimental de-
tails. This material is available free of charge via the Internet
at http://pubs.acs.org.
Figure 2. (a) Overlay of SEC of the four dendrimers 7, 9, 10, and
11 and (b) MALDI-MS spectrum of dendrimer 10.
OL050040D
(18) Dendrimer synthesis has been successful with DCC as the amide
coupling reagent: Ashton, P. R.; Hounsell, E. F.; Jayaraman, N.; Nilsen,
T. M.; Spencer, N.; Stoddart, J. F.; Young, M. J. Org. Chem. 1998, 63,
3429.
(19) Dendrimer synthesis has been successful with TFFH as the amide
coupling reagent: (a) Ritzen, A.; Frejd, T. Chem. Commun. 1999, 2, 207.
(b) Ritzen, A.; Frejd, T. Eur. J. Org. Chem. 2000, 22, 3771.
compound 4 yielded the fully protected AB8 wedge (6) in
excellent yield as shown in Scheme 3.
The core of the dendrimer was synthesized by tetraalkyl-
ation of 1,2-propanediamine in neat benzyl acrylate. The
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Org. Lett., Vol. 7, No. 7, 2005