Functional group diversity in dendrimers

Article abstract of DOI:10.1021/ol026746e

(graph presented) A methodology for synthesizing dendrons with different peripheral functionalities is described. The benzyl ether-based dendrons reported here were synthesized using allyl and methoxymethyl ether-based protection-deprotection strategies.

Full text of DOI:10.1021/ol026746e

ORGANIC
LETTERS
2002
Vol. 4, No. 21
3751-3753
Functional Group Diversity in
Dendrimers†
Kulandaivelu Sivanandan, Dharmarao Vutukuri, and S. Thayumanavan*
Department of Chemistry, Tulane UniVersity, New Orleans, Louisiana 70118
thai@tulane.edu
Received August 19, 2002
ABSTRACT
A methodology for synthesizing dendrons with different peripheral functionalities is described. The benzyl ether-based dendrons reported
here were synthesized using allyl and methoxymethyl ether-based protection−deprotection strategies.
Significant effort has been devoted over the past decade to
achieve molecular architectures inspired by Nature.1 Most
biological scaffolds are macromolecular in dimension and
exhibit excellent control over size, shape, and functional
group displays. Dendrimers belong to a unique class of
artificial structural motifs that fit the requirement of con-
trolled size.2 Due to the globular shape at higher generations,
dendrimers have often been referred to as possible globular
protein mimics.3 However, exquisite control of functional
group presentations in dendrimers has not been fully
explored. Therefore, to further develop dendrimers as
potential biomimetics, they should exhibit other important
structural features beyond globular conformation and con-
trolled molecular weight.
We have previously described a molecular design based
on benzyl ether dendrimers in which functional groups can
be directed selectively toward the macromolecular interior.4
It is equally important that opportunities for diversity among
these functional groups are made available. Due to the
iterative nature of the dendrimer synthesis, it is easy to
imagine varying the functionalities in each layer of the
dendrimer. However, the versatility of dendrimers as bio-
mimetics will increase if we gain the ability to vary each of
the monomer units within these benzyl ether dendrimers.5
In this work, we show the synthesis of dendrons up to a
third generation in which eight different peripheral units are
incorporated. Note that synthesis of a dendrimer, in which
each of the peripheral monomers is different, is an indirect
demonstration of the ability to vary each of the monomer
units within the dendrimer. Therefore, this strategy can be
used to generate dendrimers in which every monomer unit
is different.
† This paper is dedicated to Professor Jeffrey S. Moore on the occasion
of his 40th birthday.
(1) (a) Breslow, R. Acc. Chem. Res. 1995, 28, 146-153. (b) Cram, D.
J. Nature 1992, 356, 29-36. (c) Rebek, J. Acc. Chem. Res. 1999, 32, 278-
286. (d) Gellman, S. H. Acc. Chem. Res. 1998, 31, 173-180. (e) Hill, D.
J.; Mio, M. J.; Prince, R. B.; Hughes, T. S.; Moore, J. S. Chem. ReV. 2001,
101, 3893-4012. (f) Nowick, J. S. Acc. Chem. Res. 1999, 32, 287-296.
(2) (a) Newkome, G. R.; Moorefield, C. N.; Vo¨gtle, F. Dendrimers and
Dendrons: Concepts, Syntheses, Applications; Wiley-VCH: Weinheim,
Germany, 2001. (b) Bosman, A. W.; Janssen, H. M.; Meijer, E. W. Chem.
ReV. 1999, 99, 1665-1688. (c) Brunner, H. J. Organomet. Chem. 1995,
500, 39-46. (d) Grayson, S. M.; Fre´chet, J. M. J. Chem. ReV. 2001, 101,
3819-3868. (e) Fischer, M.; Vo¨gtle, F. Angew. Chem., Int. Ed. 1999, 38,
884-905. (f) Zeng, F.; Zimmerman, S. C. Chem. ReV. 1997, 97, 1681-
1712.
To further our ultimate goal of diversifying functional
group placements in our own molecular design,4 the den-
drimers reported herein are benzyl ether-based and con-
vergently2d,6 assembled. The building blocks used in the
(4) Bharathi, P.; Zhao, H.; Thayumanavan, S. Org. Lett. 2001, 3, 1961-
1964.
(5) For a methodology, involving triazine-based dendrimers, that is
capable of differentiating every monomer, see: Zeng, W.; Nowlan, D. T.,
III; Thomson, L. M.; Lackowski, W. M.; Simanek, E. E. J. Am. Chem.
Soc. 2001, 123, 8914-8922.
(3) (a) Smith, D. K.; Diederich, F. Chem. Eur. J. 1998, 4, 1353-1361
and references therein. (b) Enomoto, M.; Aida, T. J. Am. Chem. Soc. 2002,
124, 6099-6108.
10.1021/ol026746e CCC: $22.00 © 2002 American Chemical Society
Published on Web 09/18/2002

Table 1. Yields for Steps Shown in Scheme 1
step i
step ii
step iii
step iv
R1
R2
(% yield)
(% yield)
(% yield)
(% yield)
2-5a
2-5b
2-5c
2-5d
o-Me-C6H4
p-t-Bu-C6H4
m-Me-C6H4
n-C9H19
p-Br-C6H4
m-Cl-C6H4
m-Br-C6H4
C6H5
95
92
84
82
64
67
84
82
95
86
88
84
92
86
88
82
synthesis of these dendrimers involve AB2 units. To be able
to differentiate each of the monomer units within the
dendrimer, only one of the two B functionalities should be
reactive. Therefore, we have protected one of the two
phenolic groups in 3,5-dihydroxybenzyl alcohol. Utilizing
protection-deprotection strategies in dendrimer synthesis
increases the number of steps in the assembly. However, we
rationalized that the benefits of being able to differentiate
each monomer in the dendrimer far outweigh the rather small
increase in the number of synthetic steps.
To obtain a G-3 dendron in which all eight functionalities
are different, four unsymmetrically substituted G-1 dendrons
were synthesized. The repeating unit for the synthesis was
3-allyloxy-5-hydroxybenzyl alcohol (1). Treatment of 1 with
1 equiv of benzyl halides or alkyl halides in the presence of
potassium carbonate and 18-crown-6 in acetone afforded the
monosubstituted products 2a-d in 82-95% yields (Scheme
1, Table 1). Deprotection of the allyl functionality was carried
in the aryl ring are used as the second electrophile. If these
were used in the first step, the allyl deprotection afforded
impure product mixtures. We ascribe the impurities to the
possible hydrodehalogenation upon treatment with Pd(PPh3)4
and sodium borohydride.
Treatment of the 3-mer benzyl alcohols 4a-d with
triphenylphosphine and N-bromosuccinimide in THF af-
forded the corresponding bromomethyl compounds 5a-d in
82-92% yields (Scheme 1, Table 1). This conversion has
been previously reported using Ph3P/CBr4, Ph3P/NBS (in
DMF), PBr3, etc.6,8 In our case, all these protocols provided
inconsistent and low yields. However, when attempted in a
concentrated solution in THF, our reaction was complete in
less than five minutes. We also noticed that the products
decomposed if the reaction was allowed to proceed for longer
times.
Sequential treatment of 5d with 1 followed by the
deprotection of the allyl group and treatment with 5c afforded
the 7-mer dendron 6a in 92, 87, and 89% yields, respectively
(Scheme 2). However, coupling of 5a and 5b to obtain 6b
Scheme 1. Assembly of 3-mer Dendronsa
Scheme 2. Synthesis of 7-mer Dendronsa
a (i) K2CO3, 18-crown-6, acetone, reflux, (92% with 5d, 94%
with 5a); (ii) for P = allyl, Pd(PPh3)4, NaBH4, THF, 87%; for P =
Mom, Dowex® 50W-X8, H+ form resin, dioxane, H2O, reflux, 64%;
(iii) K2CO3, 18-crown-6, acetone, reflux, (89% with 5c, 92% with
5b) (iv) Ph3P, NBS, THF (86% with 6a, 92% with 6b).
a (i) R1CH2-X, K2CO3, 18-crown-6, acetone, reflux; (ii)
Pd(PPh3)4, NaBH4, THF; (iii) R2CH2-X, K2CO3, 18-crown-6,
acetone, reflux; (iv) Ph3P, NBS, THF.
using the current synthetic sequence requires subjecting a
dendron containing an aryl halide moiety to the palladium-
catalyzed deprotection conditions, to which they are incom-
patible. Therefore, we resorted to an alternate protecting
group, MOM-ether. Monoprotected dihydroxybenzyl alcohol
out with sodium borohydride in the presence of a catalytic
amount of Pd(PPh3)4 to provide products 3a-d in 64-84%
yields (Scheme 1, Table 1).7 Treatment of 3 with a different
set of benzyl bromides afforded products 4a-d in 84-95%
yields (Scheme 1, Table 1). Note that in this reaction
sequence, the benzyl bromides that contain a halide moiety
(6) Hawker, C. J.; Fre´chet, J. M. J. J. Am. Chem. Soc. 1990, 112, 7638-
7647.
(7) For the allyl deprotection methodology, see: Beugelmans, R.;
Bourdet, S.; Bigot, A.; Zhu, J. Tetrahedron Lett. 1994, 35, 4349-4350.
(8) van Bommel, K. J. C.; Metselaar, G. A.; Verboom, W.; Reinhoudt,
D. N. J. Org. Chem. 2001, 66, 5405-5412.
3752
Org. Lett., Vol. 4, No. 21, 2002

Treatment of 6a and 6b with Ph3P and NBS in THF
afforded the corresponding bromomethyl compounds 8a and
8b in 86 and 92% yields, respectively. Reaction of 8a with
7, followed by deprotection of the MOM-ether and treatment
with 8b afforded the 15-mer dendron 10 in 80, 77, and 79%
yields, respectively (Scheme 3). Note that all eight peripheral
groups in 10 are different from each other.
Scheme 3. Synthesis of 15-mer Dendronsa
In summary, we have developed a simple synthetic
methodology in which all the monomer units within the
dendrimer can be differentiated. We have demonstrated this
method by synthesizing a dendron in which all the peripheral
groups are different. This approach will open up several
opportunities for dendrimers. For example, Schlu¨ter and co-
workers have elegantly developed polymers containing
dendritic side chains.9 The current methodology will offer
the opportunity to synthesize polymers where dendrimers are
main chain components.10 Also, there have been reports that
demonstrate one or two functionalities in the periphery of
the dendrimer in a controlled or an uncontrolled fashion.5,11
The current methodology will offer the opportunity to
diversify those functionalities. Meijer, Zimmerman, and
Astruc have performed host-guest binding studies based on
specific functional groups in the periphery or core.12 The
ability to present different functional groups at the dendrimer
surface should significantly further such a repertoire.
Acknowledgment. This work was supported by the
National Institutes of Health (NIGMS). S.T. is a Cottrell
Scholar (Research Corporation) and a NSF-Career awardee.
Infrastructural support through the Center for Microfabrica-
tion (NSF-EPSCoR) and Tulane Institute for Macromolecular
Science and Engineering (NASA) is acknowledged.
Supporting Information Available: Experimental details
and characterization data for all the compounds reported. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL026746E
(9) (a) Karakaya, B.; Claussen, W.; Gessler, K.; Saenger, W.; Schlu¨ter,
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a (i) K2CO3, 18-crown-6, acetone, reflux, 7, 80%; (ii) Dowex®
50W-X8, H+ form resin, methanol/dioxane 1:1, water, reflux, 77%;
(iii) K2CO3, 18-crown-6, acetone, reflux, 8b, 79%.
(12) (a) Baars, M. W. P. L.; Karlsson, A. J.; Sorokin, V.; de Waal, B. F.
W.; Meijer, E. W. Angew. Chem., Int. Ed. 2000, 39, 4262-4265. (b) de
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Blais, J. C.; Astruc, D. J. Am. Chem. Soc. 1997, 119, 2588-2589. (d)
Zimmerman, S. C.; Zeng, F.; Reichert, D. E. C.; Kolotuchin, S. V. Science
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Chem. 2001, 217, 95-120.
7 was treated with 5a to afford the monosubstituted product
in 94% yield. Deprotection of the MOM-ether using a Dowex
resin was achieved in 64% yield. Treatment of the resulting
phenol with 5b afforded the product 6b in 92% yield
(Scheme 2).
Org. Lett., Vol. 4, No. 21, 2002
3753