A rapid, orthogonal synthesis of poly(benzyl ester) dendrimers via an "activated" monomer approach

Article abstract of DOI:10.1021/ol9907724

(Matrix presented) Herein we introduce the concept of an "activated" monomer approach to the synthesis of convergent dendrimers. In this method a set of chemically orthogonal monomers, one of which is an "activated" analogue of the other, is used to rapid

Full text of DOI:10.1021/ol9907724

ORGANIC
LETTERS
1
999
Vol. 1, No. 4
85-687
A Rapid, Orthogonal Synthesis of
Poly(benzyl ester) Dendrimers via an
6
“Activated” Monomer Approach
Adam W. Freeman and Jean M. J. Fr e´ chet*
Department of Chemistry, UniVersity of California, Berkeley, California 94720-1460
frechet@cchem.berkeley.edu
Received June 29, 1999
ABSTRACT
Herein we introduce the concept of an “activated” monomer approach to the synthesis of convergent dendrimers. In this method a set of
chemically orthogonal monomers, one of which is an “activated” analogue of the other, is used to rapidly synthesize large, perfect dendrimers
with one additional generation being added in each reaction. This method is exemplified by the efficient preparation of a new family of
poly(benzyl ester) dendrimers described below.
Despite the tremendous structural and architectural diversity
found in dendrimers,1-3 only two primary synthetic meth-
odologies have been developed for their preparation, either
which precludes the need for activation of surface or focal
point moieties to continue dendrimer growth, allows large,
perfect dendrimers to be prepared in only a few transforma-
4
5,6
12,13
divergent or convergent approaches. Several clever strate-
gies have been devised to accelerate the normal stepwise
activation/coupling sequences employed in both methods.
tions.
Herein we describe the synthesis of a set of monomers
based on 5-(hydroxymethyl)isophthalic acid 2 (Scheme 1).
The AB monomers 3 and 4 are chemically orthogonal and
2
thus can afford large, perfect dendrons and dendrimers at
the rate of one generation per coupling reaction. Because
these monomers are already “activated” with respect to
reaction with one another, once incorporated into the
monodendron, growth can continue without the need for
further activation.
7,8
These include the double-stage convergent and double
9
exponential growth approaches, as well as the use of AB
building blocks (typically n g 4) termed “hypermono-
n
mers”.1
0,11
The use of chemically orthogonal monomers,
(1) Newkome, G. R.; Moorefield, C. N.; V o¨ gtle, F. Dendritic Macro-
molecules; VCH: New York, 1996 and references therein.
(
(
2) Fr e´ chet, J. M. J. Science 1994, 263, 1710 and references therein.
3) Matthews, O. A.; Shipway, A. N.; Stoddart, J. F. Prog. Polym. Sci.
Both monomers chosen are derived from 5-(hydroxy-
14
1
998, 23, 1.
4) Tomalia, D. A.; Baker, H.; Dewald, J.; Hall, M.; Kallos, C.; Martin,
S.; Roeck, J.; Ryder, J.; Smith, P. Polym. J. 1985, 17, 117.
5) Hawker, C.; Fr e´ chet, J. M. J. J. Chem. Soc., Chem. Commun. 1990,
010.
methyl)isophthalic acid 2, itself made from the correspond-
ing commercially available diethyl ester 1. Hence, saponi-
fication of the diester with aqueous KOH in a refluxing
(
(
1
(
(
6) Hawker, C. J.; Fr e´ chet, J. M. J. J. Am. Chem. Soc. 1990, 112, 7638.
7) Wooley, K. L.; Hawker, C. J.; Fr e´ chet, J. M. J. J. Am. Chem. Soc.
(10) Wooley, K. L.; Hawker, C. J.; Fr e´ chet, J. M. J. Angew. Chem., Int.
Ed. Engl. 1994, 33, 82.
1
991, 113, 4252.
8) Ihre, H.; Hult, A.; Fr e´ chet, J. M. J.; Gitsov, I. Macromolecules 1998,
1, 4061.
9) Kawaguchi, T.; Walker, K. L.; Wilkins, C. L.; Moore, J. S. J. Am.
Chem. Soc. 1995, 117, 2159.
(11) L’abb e´ , G.; Forier, B.; Dehaen, W. J. Chem. Soc., Chem. Commun.
1996, 58, 1262.
(12) Spindler, R.; Fr e´ chet, J. M. J. J. Chem. Soc., Perkins Trans. 1 1993,
913.
(
3
(
(13) Zeng, F.; Zimmerman, S. C. J. Am. Chem. Soc. 1996, 118, 5326.
1
0.1021/ol9907724 CCC: $18.00 © 1999 American Chemical Society
Published on Web 07/20/1999

Scheme 1
Scheme 2a
mixture of MeOH and dioxane afforded the hydroxy acid 2
in 65% yield. Titration of 2 with methanolic KOH followed
by removal of the solvent and several azeotropes with
benzene quantitatively yielded monomer 3. The comple-
mentary activated monomer 4 was prepared from 2 in 85%
yield by first protecting the carboxyl groups of 2 as their
trimethylsilyl esters, followed by in situ chlorination of the
15
2
remaining hydroxymethyl moiety with SOCl . Both mono-
mers 3 and 4 were isolated as shelf-stable, white solids.
Monomers 3 and 4 were designed to promote the rapid
growth of high-generation dendrons via an iterative and
alternating sequence of carboxylate salt alkylations and DCC/
16
DPTS-mediated esterifications, respectively. The reactions
were selected because they are known to be extremely mild,
fast, and afford high conversions. More importantly, the use
of these conditions is generally not accompanied by com-
plicating side products. Of utmost importance is the fact that
the reaction conditions required for introduction of one
monomer do not adversely affect functionality already
present within either the dendrimer or the complementary
monomer.
a
(i) 18-crown-6, K CO , CH CN, ∆; (ii) DCC, DPTS, CH Cl ,
2
3
3
2
2
THF; (iii) KBr, DIPEA (1 drop), DMF, 80 °C.
catalytic DPTS cleanly yielded the [G-2] chloride 6 in 86%
yield after purification. The third-generation alcohol 7 was
prepared by alkylation of the carboxylates of 3 with a slight
3
excess of monodendron 6. Unlike the preparation of 5, CH -
The orthogonal coupling sequence used to prepare con-
vergent poly(benzyl ester) dendrimers based upon monomers
CN could not be used for this alkylation due to the poor
solubilities of both the starting and product dendrons. Use
of either refluxing acetone or 2-butanone, both better solvents
for the dendrons, resulted in sluggish reactions that were
accompanied by the formation of increased amounts of side
products (presumably the result of increased ester hydrolysis
or transesterification). However, by employing anhydrous
DMF as solvent, a stoichiometric amount of KBr, and 1 drop
of N,N-diispropylethylamine (DIPEA), both the solubility and
reactivity were enhanced so extensively that high conversions
were observed within less than 1 h at 80 °C. These conditions
proved to be so efficient and general that they were used
throughout the remainder of the syntheses. In this way the
3
and 4 possessing benzyl ester surfaces is depicted in
Scheme 2. Thus, refluxing 3 and benzyl bromide in CH CN
3
in the presence of a catalytic amount of 18-crown-6 afforded
the [G-1] alcohol 5 in 94% yield within 2 h. Coupling of
alcohol 5 with monomer 4 in the presence of DCC and
(14) The only reference for the use of 2 in dendrimers was reported by
Seebach, D.; Herrmann, G. F.; Lengweiler; U. D.; Amrein, W. HelV. Chem.
Acta 1997, 80, 989.
(15) The preparation of other chloro acids using this method has been
previously reported by Shiozaki, M.; Ishida, N.; Iino, K.; Hiraoka, T.
Tetrahedron 1980, 36, 2735.
(16) Moore, J. S.; Stupp, S. I. Macromolecules 1990, 23, 65.
686
Org. Lett., Vol. 1, No. 4, 1999

[G-3] alcohol 7 was prepared in 89% yield after purification.
Finally, condensation of 7 with monomer 4 using the same
DCC/DPTS conditions as described above afforded the [G-4]
chloride 8, again in excellent yield (90%) after purification.
Scheme 4
The versatility of this approach was demonstrated by the
fact that the synthesis of these dendrons could begin with
either monomer 3 or 4. In this way, starting from benzyl
alcohol and monomer 4, the complementary dendrons
(
[G-1]
E
-Cl 9 (97%), [G-2]
E E
-OH 10 (81%), [G-3] -Cl 11
(
85%), [G-4]
E
-Cl 12 (84%)) could be prepared using the
same chemistry described above with similar yields observed
for each step (Scheme 3).
Scheme 3
In addition, perfect dendrimers based upon these poly-
(benzyl ester) monodendrons were prepared, again using the
same coupling conditions described above. Thus coupling
dendron 7 with trimesic acid in the presence of DCC/DPTS
afforded the [G-3] tricore dendrimer 13 very cleanly in 85%
yield after purification by flash chromatography (Scheme 4).
While all of the dendrons and dendrimers described herein
were purified by flash chromatography, it must be empha-
sized that the clean and highly converting nature of the
reactions employed facilitated product isolation. The small
amounts of impurities formed were generally more polar than
the product dendrons and hence could be removed with
relative ease. The combination of the orthogonal “activated”
monomer strategy, the fast reactions employed, and the ease
of purification makes it possible to prepare large dendrimers
is extremely general and will find widespread applicability
in the synthesis of many families of dendrimers including
aliphatic polyesters and polyethers. While the poly(benzyl
ester) dendrimers described herein clearly lack the structural
1-3
robustness of some of their predecessors, the facility with
which they can be synthesized may offset these weaknesses.
This family of dendrimers will surely find uses as molecular
1
7
18
scaffolds, as building blocks for site isolation, or in
materials applications where eventual degradation of the
1
9
(i.e., [G-4]) of this type in as little as 3 days. The structure
dendrimer is desired.
and purity of all the dendrons described herein has been
Acknowledgment. This research was supported by a
grant from the AFOSR MURI program. Additional fellow-
ship support from Lucent Technologies for A.W.F. is
gratefully acknowledged.
1
13
confirmed using H and C NMR, mass spectroscopy (EI
MS for [G-1] dendrons and MALDI-TOF MS for all others),
and elemental analyses.
In conclusion, we have introduced to the concept of the
orthogonal “activated” monomer approach for the rapid
synthesis of large, perfect dendrimers and demonstrated that
this, in combination with judicious choices of chemical
reactions, can be used to efficiently prepare a new family of
poly(benzyl ester) dendrimers. We believe that this strategy
OL9907724
(17) Leon, J. W.; Kawa, M.; Fr e´ chet, J. M. J. J. Am. Chem. Soc. 1996,
118, 8847.
(
(
18) Kawa, M.; Fr e´ chet, J. M. J. Chem. Mater. 1998, 10, 286.
19) Wendland, M. S.; Zimmerman, S. C. J. Am. Chem. Soc. 1999, 121,
1389.
Org. Lett., Vol. 1, No. 4, 1999
687