Synthesis and Self-Assembly of Supramolecular Dendritic "Bow-Ties": Effect of Peripheral Functionality on Association Constants

Article abstract of DOI:10.1021/jo035329s

Self-assembled polyester dendritic bow-ties with various peripheral groups were prepared, and their association constants were measured by ¹H NMR in CDCl₃. The two complementary dendrons were prepared by attachment of either a bis(ad

Full text of DOI:10.1021/jo035329s

Syn th esis a n d Self-Assem bly of Su p r a m olecu la r Den d r itic
“Bow -Ties”: Effect of P er ip h er a l F u n ction a lity on Associa tion
Con sta n ts
Elizabeth R. Gillies and J ean M. J . Fre´chet*
Center for New Directions in Organic Synthesis, Department of Chemistry, University of California,
Berkeley, California 94720-1460
frechet@cchem.berkeley.edu
Received September 9, 2003
Self-assembled polyester dendritic bow-ties with various peripheral groups were prepared, and
their association constants were measured by 1H NMR in CDCl3. The two complementary dendrons
were prepared by attachment of either a bis(adamantylurea) or a glycinylurea to the focal point of
the dendron. The parent self-assembled system with benzylidene acetals on one periphery and
isopropylidene acetals on the other had an association constant of 520 M-1. Upon deprotection of
one dendron, the association constant is increased by more than an order of magnitude as the
solubility of the hydroxyl-terminated dendron in CDCl3 is decreased. In contrast, attachment of
tri(ethylene oxide) units to the periphery of one dendron lowers the association constant by almost
an order of magnitude. The causes of these relatively large changes in complex strength are
discussed in terms of solubility, steric effects, competitive hydrogen bonding, and the structure of
the dendritic scaffold.
In tr od u ction
major challenges to their widespread application remains
the large amount of synthetic effort required to attain
well-defined, high molecular weight, functional dendritic
structures. Therefore, inspired by nature’s ability to
gather relatively simple components into larger, more
complex assemblies, researchers have sought to make use
of the tool of molecular recognition to assemble dendritic
architectures more efficiently.
Thus far, a range of noncovalent interactions have been
exploited for the preparation of self-assembled dendrim-
ers. The hydrogen bond mediated assembly, as first
introduced by Zimmerman and co-workers, consisted of
Fre´chet-type benzyl ether dendrons with two isophthalic
acid units at their focal point6 but has since expanded to
include other units such as naphthyridine,7 ureidode-
azapterin,8 melamine, cyanuric acid,9 and DNA oligo-
mers10 at the focal point. Metal-templated assemblies
have also been investigated, such as those based on a
Ru(II)-terpyridine system,11 an iron-sulfur core,12 or the
complexation of lanthanide ions by carboxylic acids.13
In recent years, the application of dendritic structures
has expanded to include a diverse array of fields includ-
ing drug delivery,1 diagnostics,2 catalysis,3 and photo- or
electroactive materials.4 Despite the great advances in
synthetic methods for preparing dendrimers,5 one of the
(1) (a) Liu, M.; Fre´chet, J . M. J . Pharm. Sci. Technol. Today 1999,
2, 393-401. (b) Malik, N.; Wiwattanapatapee, R.; Klopsch, R.; Lorenz,
K.; Frey, H.; Weener, J . W.; Meijer, E. W.; Paulus, W.; Duncan, R. J .
Controlled Release 2000, 65, 133-148. (c) Esfand, R.; Tomalia, D. A.
Drug Discovery Today 2001, 6, 427-436. (d) Padilla De J esu´s, O. L.;
Ihre, H. R.; Gagne, L.; Fre´chet, J . M. J .; Szoka, F. C. J . Bioconjugate
Chem. 2002, 13, 453-461. (e) Gillies, E.; Fre´chet, J . M. J . Chem.
Commun. 2003, 1640-1641.
(2) (a) Stiriba, S.-E.; Frey, H.; Haag, R. Angew. Chem., Int. Ed. 2002,
41, 1329-1334. (b) Krause, W.; Hackmann-Schlichter, N.; Maier, F.
K.; Mu¨ller, R. Top. Curr. Chem. 2000, 210, 261-308.
(3) (a) Liang, C. O.; Helms, B.; Hawker, C. J .; Fre´chet, J . M. J . Chem.
Commun. 2003, 2524-2525. (b) Hecht, S.; Fre´chet J . M. J . J . Am.
Chem. Soc. 2001, 123, 6959-6960. (c) Piotti, M. E.; Rivera, F.; Bond,
R.; Hawker, C. J .; Fre´chet, J . M. J . J . Am. Chem. Soc. 1999, 121, 9471-
9472. (d) Hecht, S.; Fre´chet, J . M. J . Angew. Chem., Int. Ed. 2001, 40,
74-91. (e) Twyman, L. J .; King, A. S.; Martin, I. K. Chem. Soc. Rev.
2002, 31, 69-82. (f) Astruc, D.; Chardac, F. Chem. Rev. 2001, 101,
2991-3023.
(4) (a) Freeman, A. W.; Koene, S. C.; Malenfant, P. R. L.; Thompson,
M. E.; Fre´chet, J . M. J . J . Am. Chem. Soc. 2000, 122, 12385-12386.
(b) Kawa, M.; Fre´chet, J . M. J . Chem. Mater. 1998, 10, 286-296. (c)
Cameron, C. S.; Gorman, C. B. Avd. Funct. Mater. 2002, 12, 17-20.
(d) J uris, A.; Venturi, M.; Ceroni, P.; Balzani, V.; Campagna, S.;
Serroni, S. Collect. Czech. Chem. Commun. 2001, 66, 1-32. (e) Adronov,
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L.; Aida, T. J . Am. Chem. Soc. 1998, 120, 10895. (g) Devadoss, C.;
Bharathi, P.; Moore, J . S. J . Am. Chem. Soc. 1996, 118, 9635-9644.
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Hawker, C. J .; Fre´chet, J . M. J . J . Am. Chem. Soc. 1990, 112, 7638-
7647. (e) Hawker, C.; Fre´chet, J . M. J . J . Chem Soc., Chem. Commun.
1990, 1010-1013.
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V. Science 1996, 271, 1095-1098.
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Chem. Soc. 1998, 120, 2172-2173.
(8) Corbin, P. S.; Lawless, L. J .; Li, Z.; Ma, Y.; Witmer, M. J .;
Zimmerman, S. C. Proc. Nat. Acad. Sci. U.S.A. 2002, 99, 5099-5104.
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Sci. Eng. 1997, 77, 138-139.
(10) Goh, S. L.; Francis, M. B.; Fre´chet, J . M. J . Chem. Commun.
2002, 2954-2955.
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99, 1689-1746.
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10.1021/jo035329s CCC: $27.50 © 2004 American Chemical Society
Published on Web 11/08/2003
46
J . Org. Chem. 2004, 69, 46-53

Self-Assembly of Dendritic Bow-Ties
SCHEME 1
Hydrophobic interactions have been exploited to prepare
dendrimers based on a bis(adamantane) core and two
methyl)propionic acid using the complementary bis-
(adamantylurea)-glycinylurea system, developed by
Meijer and co-workers, at the focal point of the bow-tie.20
This system was chosen since it is not self-complemen-
tary and therefore has the potential to bring together two
orthogonally functionalized dendrons. In addition, the
association constant is in a range expected to be ap-
propriate for study by convenient 1H NMR methods.21
The synthesis of the parent dendrons having iso-
propylidene or benzylidene acetals on the periphery is
described, as well as their attachment to the focal point
adamantylurea or glycinylurea units. The peripheral
groups of the parent dendrons were altered to provide
new dendrons, and these were assembled in various
combinations to provide several different complexes. The
association constants for complex formation were mea-
sured by 1H NMR, and the effect of the changes in
peripheral functionality on the association constants was
examined.
dendrons with cyclodextrin units at the focal point.14
A
self-assembled pseudorotaxane was prepared on the basis
of cation-π interactions,15 and π-π stacking interactions
have been used to assemble benzyl ether dendrons into
well-defined structures such as cubes or cylinders.16
Although several studies have investigated the effect
of dendrimer generation on the strength of complex
association,6,7,17,18 to our knowledge there has not been
any systematic study of the effect of peripheral function-
ality at a given generation on the association constant.
We have recently been interested in dendritic bow-ties
bearing orthogonal surface functionality because of their
potential for attachment of complementary surface groups
to each side of the bow-tie and have recently reported
the covalent synthesis of such structures.19 In addition
to providing a more “convergent” route to such structures,
it was recognized that self-assembled dendritic bow-ties
would be an ideal scaffold for a study of the effect of
peripheral functionality on the association strength. It
was hoped that it would be possible to adjust the strength
of the bow-tie complex by simply altering the solubility
of an individual dendron or introducing flexible groups
on the dendrimer periphery, while maintaining a con-
stant generation.
Resu lts a n d Discu ssion
Syn th esis. In this article, the dendrons are named
using the following shorthand notation: (peripheral
group)m-[G-n]-(focal point group)p, where m is the number
of peripheral groups, n is the dendron generation, and p
is the number of focal point groups.
The (benzylidene)4-[G-3]-COOH 3b was synthesized
divergently as shown in Scheme 1 using a recently
reported anhydride coupling method.22 A trimethylsilyl-
ethyl ester was chosen as the protecting group for the
focal point acid. Therefore, trimethylsilylethanol was
coupled with the previously reported benzylidene-2,2-bis-
In this article, we report the noncovalent synthesis of
polyester dendritic bow-ties based on 2,2-bis(hydroxy-
(14) Newkome, G. R.; God´ınez, L. A.; Moorefield, C. N. Chem.
Commun. 1998, 1821-1822.
(15) Gibson, H. W.; Yamaguchi, N.; Hamilton, L.; J ones, J . W. J .
Am. Chem. Soc. 2002, 124, 4653-4665.
(16) Percec, V.; Cho, W.-D.; Ungar, G.; Yeardley, D. J . P. J . Am.
Chem. Soc. 2001, 123, 1302-1315.
(17) Cardona, C. M.; Alvarez, J .; Kaifer, A. E.; McCarley, T. D.;
Pandey, S.; Baker, G. A.; Bonzagni, N. J .; Bright, F. V. J . Am. Chem.
Soc. 2000, 122, 6139-6144.
(20) 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. Baars,
M. W. P. L.; Meijer, E. W. Top. Curr. Chem. 2000, 210, 131-182.
(21) Fielding, L. Tetrahedron 2000, 56, 6151-6170.
(22) Ihre, H.; Padilla De J esu´s, O. L.; Fre´chet, J . M. J . J . Am. Chem.
Soc. 2001, 123, 5908-5917.
(18) Smith, D. K.; Diederich, F. Chem. Commun. 1998, 2501-2502.
(19) Gillies, E. R.; Fre´chet, J . M. J . J . Am. Chem. Soc. 2002, 14137-
14146.
J . Org. Chem, Vol. 69, No. 1, 2004 47

Gillies and Fre´chet
SCHEME 2
SCHEME 3
(oxymethyl)propionic anhydride,22 in the presence of
DMAP and pyridine, to provide the benzylidene-[G-1]-
trimethylsilylethyl ester 1a . The benzylidene acetal
protecting group was then removed by catalytic hydro-
genolysis using Pd/C as catalyst to provide the (HO)2-
[G-1]-trimethylsilylethyl ester 1b. The coupling and
deprotection procedures were repeated again to give the
(HO)4-[G-2]-trimethylsilylethyl ester 2b, and one more
coupling to the anhydride provided the (benzylidene)4-
[G-3]-trimethylsilylethyl ester 3a . The trimethylsilylethyl
ester protecting group was removed using tetrabutylam-
monium fluoride (TBAF), yielding the acid 3b with four
peripheral benzylidene acetals.
converted from benzylidene acetals to hydroxyls by
hydrogenolysis to give 7.
The glycinylurea moiety was prepared as shown in
Scheme 3. Benzyl glycinate was reacted with 4-nitro-
phenyl chloroformate, yielding N-(4-nitrophenyloxycar-
bonyl)benzyl glycinate 8. This carbamate was then
reacted with 1,6-aminohexanol to provide 9, with the
desired urea moiety and a hydroxyl handle for coupling
to the dendron. The (isopropylidene)4-[G-3]-COOH 10,24
was coupled to 9 using DCC as shown in Scheme 4,
providing 11a , and the benzyl ester protecting group was
removed to give the second parent dendron 11b. Removal
of the isopropylidene acetals on the periphery of 11b was
accomplished using ceric ammonium nitrate (CAN),25 to
provide the hydroxyl-terminated dendron 13.
Oligo(ethylene oxide) units could be introduced to the
periphery of the dendron by first removing the isopro-
pylidene acetals from the benzyl ester 11a using the CAN
method to provide 13, followed by coupling with the acid-
functionalized triglyme 14, prepared as previously re-
ported,26 to give 15a . Finally, the benzyl ester protecting
To synthesize the adamantylurea moiety, the previ-
ously reported dinitrile 4a 23 was protected as the MOM
ether 4b as shown in Scheme 2, and then the nitrile
groups were reduced to amines using Raney nickel under
basic conditions. Without further purification, the amine
groups were reacted with adamantyl isocyanate to form
the bis(adamantylurea) compound 5a . The MOM protect-
ing group was then removed under acidic conditions to
provide the alcohol 5b, which could be coupled to 3b
using DCC, in the presence of DMAP and 4-dimethyl-
aminopyridinium p-toluenesulfonate (DPTS) to provide
the parent dendron 6. The periphery of 6 could be
(24) Wu¨rsch, A.; Mo¨ller, M.; Glauser, T.; Lim, L. S.; Voytek, S. B.;
Hedrick, J . L. Macromolecules 2001, 34, 6601-6615.
(25) Marko, I. E.; Ates, A.; Gautier, A.; Leroy, B.; Plancher, J .-M.;
Quesnel, Y.; Vanherck, J .-C. Angew. Chem., Int. Ed. 1999, 38, 3207-
3209.
(26) Ihre, H.; Padilla De J esu´s, O. L.; Szoka, F. C. J .; Fre´chet, J . M.
J . Bioconjugate Chem. 2002, 13, 433-452.
(23) Bell, J . A.; Kenworthy, C. Synthesis 1971, 650-652.
48 J . Org. Chem., Vol. 69, No. 1, 2004

Self-Assembly of Dendritic Bow-Ties
SCHEME 4
SCHEME 5
The dependence of chemical shift on complex concen-
tration is shown in Figure 2 for all signals but that of
proton 1, which was too broad to measure accurately at
lower concentrations. Using the appropriate curve-fitting
procedure,27 the association constant (Ka) for complex [6‚
11b] was determined to be (520 ( 90) M-1. To provide
an accurate comparison between complexes, all associa-
tion constants are reported based on the signal for the
methylene protons 6 as assigned in Figure 1, since the
association constant varies somewhat depending on the
proton investigated. This signal was chosen since it is
the only one that remains unobstructed by other peaks
throughout the titration experiment for all complexes.
Effect of P er ip h er a l Gr ou p on Com p lex F or m a -
tion . To study the effect of end groups on the association
constant of the two-component system, complex forma-
tion was attempted using the deprotected dendron 7 with
dendron 11b, leading to complex [7‚11b]. It was antici-
pated that the reduced solubility of 7 in CDCl3 would
enhance the strength of complex association. Indeed the
group was removed by catalytic hydrogenolysis to yield
the acid 15b.
Com p lex F or m a tion . The parent complex [6‚11b]
was formed by dissolving equimolar amounts of com-
1
pounds 6 and 11b in dry CDCl3. A comparison of the H
NMR spectra of 6 and 11b with that of a 51 mM solution
of complex [6‚11b] (Figure 1) shows that there is a
downfield shift for the adamantylurea hydrogen atoms
from δ 4.64 and 5.32 to δ 5.09 and 5.64, as well as a
significant broadening for these signals. The methylene
protons adjacent to the tertiary amine also shift down-
field from δ 2.37 and 2.53 to δ 2.67 and 2.78, consistent
with protonation of the amine. These results are in
agreement with those reported by Meijer.20 Somewhat
unexpectedly, the signals corresponding to the protons
on the urea group of 11b shift upfield upon complexation.
This may be a result of the dendrimer environment.
Ka of complex [7‚11b] was found to be (6800 ( 2900) M-1
,
an increase of more than an order of magnitude. It is
believed that this enhancement is due to a greater
decrease in free energy when the relatively insoluble
dendron 7 forms the soluble complex in comparison to
the free energy decrease when both dendrons are already
(27) Wilcox, C. S. In Frontiers in Supramolecular Chemistry;
Schneider, H. J ., Durr, H., Eds.; VCH: New York, 1991; pp 123-143.
J . Org. Chem, Vol. 69, No. 1, 2004 49

Gillies and Fre´chet
its eight hydroxyl groups. This increases the molecular
weight of the dendron from 1190 g/mol for 11b to 3129
g/mol for 15b and also increases the solubility of the
dendron in highly polar media including water. A review
of the literature shows that the dendrimer generation for
a number of supramolecular dendrimer systems has had
little or no effect on the complex stability,7,18,28 whereas
in others it has either enhanced or decreased the stability
of the desired complex considerably.6,17 In this system,
the combination of the tri(ethylene oxide) substituted
dendron 15b with 6 leads to complex [6‚15b], with a
considerably lower Ka amounting only to (70 ( 9) M-1
versus (520 ( 90) M-1 for the parent complex [6‚11b].
Initially this result was somewhat surprising considering
that the tri(ethylene oxide) groups are located far from
the focal point. In addition, covalent systems of the same
polyester backbone can be readily prepared from higher
generation dendrons with as many as 32 tri(ethylene
oxide) groups on the periphery.26 However, closer inspec-
tion of this particular system reveals possible explana-
tions for the observed effect. First, in comparison to other
systems where the dendrimer core and backbone are
relatively rigid, the polyester backbone and focal point
functionality of 15b are quite flexible. This may allow
for considerable backfolding of the dendrimer backbone
and tri(ethylene oxide) groups toward the focal point of
the dendron, thus sterically hindering complex formation.
In addition, a weak association of the oxygens of the tri-
(ethylene oxide) moieties with the urea hydrogens of the
core group may lower the association constant by com-
petition with dendron 6 for hydrogen bonding.
F IGURE 1. 1H NMR spectra (500 MHz) of (a) 11b, (b) 6, and
(c) 6‚11b (51 mM) in CDCl3. Proton assignments are given,
where n′ refers to the proton in the uncomplexed species.
To verify the effects observed in the previous com-
plexes, 15b was combined with the hydroxyl terminated
dendron 7 to form complex [7‚15b]. The Ka for this
system was found to be (1000 ( 300) M-1, an enhance-
ment again of more than an order of magnitude over the
value measured for complex [6‚15b], verifying the effect
of the hydroxyl functionalized periphery of 7. The effect
of the peripheral tri(ethylene oxide) groups is confirmed
by the 7-fold decrease in Ka for [7‚15b ] relative to
[7‚11b]. In fact, the Ka value for [7‚15b] is very close to
the predicted value of 965 M-1 based on a 13-fold increase
relative to the parent system due to the hydroxyl
periphery and a 7-fold decrease resulting from the tri-
(ethylene oxide) groups observed for the previous com-
plexes. Therefore, the combination of dendrons 7 and 15b
provides a confirmation of both the solubility and end
group effects.
F IGURE 2. The dependence on concentration of the chemical
shift of the methylene protons adjacent to the tertiary amine
and the urea protons of complex [6‚11b].
readily soluble. A somewhat similar effect has also been
observed in the formation of a supramolecular dendrimer
where the core by itself is insoluble in CDCl3 prior to
complexation of the dendritic arms.15 In this study,
however, the enhancement is remarkable because the
insoluble hydroxyl groups are not at the protected core
of the complex but rather at the periphery.
Con clu sion
When attempts were made to combine the fully depro-
tected dendron 12 with 6 in CDCl3, no complex formation
The first noncovalent synthesis of a polyester dendritic
bow-tie based on the monomer 2,2-bis(hydroxymethyl)-
propionic acid was reported. This system was used to
demonstrate that changes in peripheral functionality of
the dendrimer have a profound effect on the association
constant. Dendrimers therefore offer a convenient scaf-
fold to study the effect of various properties such as
solubility, steric hindrance, and competitive hydrogen
bonding on the strength of complex formation. The
1
was observed. H NMR analysis of the mixture showed
that 6 had dissolved in the CDCl3 while 12 remained fully
insoluble. This failure to form the desired complex may
be due to the extremely low solubility of 12 in CDCl3 or
to the lack of solubility of the resulting complex. Although
7 and 12 have the same peripheral groups, the more
hydrophobic focal point of 7 may help to raise its
solubility in CDCl3 just enough to enable formation of
the soluble complex.
To add steric bulk to dendron 11b, an acid-function-
alized tri(ethylene oxide) moiety was attached to each of
(28) Wang, Y.; Zeng, F.; Zimmerman, S. C. Tetrahedron Lett. 1997,
38, 5459-5462.
50 J . Org. Chem., Vol. 69, No. 1, 2004

Self-Assembly of Dendritic Bow-Ties
and then overnight at room temperature. The reaction mixture
was poured over 200 mL of ice and extracted with CH2Cl2. The
aqueous phase was adjusted to pH 12 with concentrated NaOH
and then extracted with CH2Cl2. The organic phase was dried
and evaporated to provide 1.2 g (93%) of 4b as a yellow oil. IR
(film from CH2Cl2): 2247. 1H NMR (500 MHz, CDCl3): δ 2.49
(t, 4H, J ) 6.8), 2.81 (t, 2H, J ) 5.4), 2.95 (t, 4H, J ) 6.8),
3.35 (s, 3H), 3.59 (t, 2H, J ) 5.4), 4.60 (s, 2H). 13C NMR (500
MHz, CDCl3): δ 17.3, 50.6, 53.3, 55.6, 66.6, 96.9, 118.8. MS
calcd [M + H]+ (C10H18N3O2): 212.1399. Found: (HRFAB)
212.1405. Anal. Calcd for C10H17N3O2: C, 56.85; H, 8.11; N,
19.89. Found: C, 56.49; H, 8.32; N, 19.54.
information obtained from these systems can be very
useful for the future design of self-assembling systems.
In particular, future work will focus on the use of
knowledge gained from this system for the synthesis of
well-defined, noncovalent dendritic structures with higher
association constants. In addition, in the future we hope
to use such concepts for the formation of supramolecular
dendrimers in polar protic solvents such as water.
Exp er im en ta l Section
Bis(a d a m a n tylu r ea ) Meth oxym eth yl Eth er (5a ). Com-
pound 4b (0.40 g, 1.9 mmol) was dissolved in 5 mL of 95%
EtOH containing 0.28 g of NaOH. Raney nickel (0.2 g) was
added as a slurry in water, and the reaction mixture was
stirred under a hydrogen atmosphere at 50 psi overnight. The
reaction mixture was carefully filtered through a glass filter,
and the catalyst was washed with EtOH. The filtrate was
concentrated, and the resulting residue was taken up in 10
mL of water. Saturated NaOH was added until the amine
began to oil out, and the mixture was extracted with CHCl3
until no more amine appeared in the CHCl3 extract by TLC.
The organic layers were dried and evaporated to provide 0.23
g of the diamine. Without further purification, the diamine
(0.23 g) was dissolved in 5 mL of CH2Cl2, and adamantyl
isocyanate (0.57 g, 3.2 mmol) was added. The reaction mixture
was stirred at room temperature overnight and then evapo-
rated. The product was purified by column chromatography
using EtOAc/MeOH (80/20) to afford 0.52 g (48% overall) of
5a as a colorless glass. IR (film from CH2Cl2): 3342, 1630,
1562. 1H NMR (500 MHz, CDCl3): δ 1.58-1.65 (m, 16H), 1.93-
1.97 (m, 12H), 2.01-2.40 (m, 6H), 2.47 (t, 4H, J ) 6.2), 2.59
(t, 2H, J ) 5.7), 3.17 (t, 4H, J ) 6.2), 3.36 (s, 3H), 3.61 (t, 2H,
J ) 5.7), 4.63 (s, 2H), 4.66 (s, 2H), 5.58 (s, 2H). 13C NMR (125
MHz, CDCl3): δ 27.3, 29.8, 36.7, 39.0, 42.8, 50.8, 52.7, 53.3,
55.7, 65.8, 96.8, 158.1. MS calcd [M + H]+ (C32H56N5O4):
574.4332. Found: (HRFAB) 574.4324. Anal. Calcd for
Ben zylid en e-[G-1]-tr im eth ylsilyleth yl Ester (1a ) a n d
R ep r esen t a t ive E st er ifica t ion P r oced u r e. Trimethyl-
silylethanol (1.4 mL, 1.0 equiv, 9.7 mmol) and DMAP (0.29 g,
0.24 equiv, 2.3 mmol) were dissolved in 60 mL of CH2Cl2, and
10 mL of pyridine was added. Benzylidene-2,2-bis(oxymethyl)-
propionic anhydride (5.0 g, 12 mmol, 1.2 equiv), prepared as
previously reported,20 was added, and the reaction mixture was
stirred at room temperature overnight. The excess anhydride
was quenched by stirring the reaction mixture with 5 mL of a
1:1 pyridine/water solution overnight. The organic phase was
diluted with CH2Cl2 and washed with 1 M NaHSO4, 10% Na2-
CO3, and saturated brine. The organic layer was dried and
evaporated to give 2.91 g (92%) of 1a as a white solid. Mp:
1
55-56 °C. IR (film from CH2Cl2): 1730. H NMR (500 MHz,
CDCl3): δ 0.06 (s, 9H), 1.03 (s, 3H), 1.06-1.08 (m, 2H), 3.64
(d, 2H, J ) 11.5), 4.28-4.31 (m, 2H), 4.67 (d, 2H, J ) 11.5),
5.45 (s, 1H), 7.33-7.34 (m, 3H), 7.44-7.46 (m, 2H). 13C NMR
(125 MHz, CDCl3): δ -1.1, 17.5, 18.1, 42.5, 63.7, 73.8, 102.0,
126.5, 128.4, 129.2, 138.1, 174.4. MS calcd [M + Li]+ (C17H26
-
LiO4Si): 329.1760. Found: (FABHR) 329.1753. Anal. Calcd
for C17H26O4Si: C, 63.32; H, 8.13. Found: C, 63.48; H, 8.02.
(HO)2-[G-1]-tr im eth ylsilyleth yl Ester (1b) a n d Rep r e-
sen ta tive Ben zylid en e Dep r otection P r oced u r e. Com-
pound 1a (0.95 g, 3.0 mmol) was dissolved in 10 mL of CH2Cl2
and diluted with 10 mL of methanol, and 95 mg of 10% w/w
Pd/C was added. The apparatus for catalytic hydrogenolysis
was evacuated and filled with H2 three times. After vigorous
stirring overnight the catalyst was filtered off in a glass filter
and was carefully washed with methanol. The filtrate was
evaporated to give 0.66 g (96%) of 1b as a white solid. Mp:
C
32H55N5O4: C, 66.98; H, 9.66; N, 12.21. Found: C, 66.66; H,
9.67; N, 12.04.
Bis(a d a m a n tylu r ea ) Alcoh ol (5b). Compound 5a (0.10 g,
0.17 mmol) was dissolved in 10 mL of MeOH, and several drops
of HCl were added. The solution was heated at 60 °C for 6 h,
then cooled, and quenched with NEt3. The solution was
concentrated to low volume, and the resulting residue was
taken up in CH2Cl2 and washed with 0.1 M NaOH. The organic
phase was dried and evaporated to give 90 mg (98%) of 5b as
a white solid. Mp > 190 °C. IR (film from CH2Cl2): 3330, 1633,
1560. 1H NMR (500 MHz, CDCl3): 1.50-1.72 (m, 16H), 1.81-
1.97 (m, 12H), 2.02 (br s, 6H), 2.41 (t, 4H, J ) 7.1), 2.47 (t,
2H, J ) 6.0), 3.21 (t, 4H, J ) 6.9), 3.61 (t, 2H, J ) 6.0), 5.17
(s, 2), 5.96 (s, 2). 13C NMR (125 MHz, CDCl3): 27.4, 29.8, 36.7,
38.4, 42.7, 50.6, 52.2, 56.2, 58.5, 158.9. MS calcd [M + H]+
(C30H52N5O3): 530.4070. Found: (HRFAB) 530.4072. Anal.
Calcd for C30H51N5O3: C, 68.01; H, 9.70; N, 13.22. Found: C,
68.18; H, 9.50; N, 12.88.
(Ben zylid en e)4-[G-3]-(a d a m a n tylu r ea )2 (6). The alcohol
5b (0.10 mg, 0.19 mmol, 1.0 equiv) and the acid 3b (0.34 g,
0.29 mmol, 1.5 equiv) were dissolved in 10 mL of CH2Cl2.
DMAP (4.6 mg, 38 µmol, 0.20 equiv) and 4-dimethylaminopy-
ridinium p-toluenesulfonate (DPTS) (12 mg, 38 µmol, 0.20
equiv) were added, followed by DCC (78 mg, 0.38 mmol, 2.0
equiv), and the reaction mixture was stirred at room temper-
ature overnight under a nitrogen atmosphere. The reaction
mixture was filtered to remove the dicyclohexylurea (DCU)
byproduct, and the filtrate was concentrated. The product was
purified by column chromatography using a solvent gradient
from EtOAc/MeOH (90/10) to EtOAc/MeOH (80/20) to afford
0.32 g (71%) of 6 as a colorless glass. IR (film from CH2Cl2):
3350, 1742, 1640. 1H NMR (500 MHz, CDCl3): δ 0.92 (s, 12H),
1.03 (s, 3H), 1.21 (s, 6H), 1.50-1.54 (m, 4H), 1.62 (s, 12H),
1.90 (s, 12H), 1.20 (s, 6H), 2.37 (t, 4H, J ) 5.8), 2.53 (t, 2H, J
1
53-55 °C. IR (film from CH2Cl2): 3330, 1720. H NMR (500
MHz, CDCl3): δ 0.06 (s, 9H), 0.99-1.03 (m, 2H), 1.04 (s, 3H),
3.04 (br s, 2H), 3.68 (dd, 2H, J ) 11.2, 4.2), 3.87 (dd, 2H, J )
11.1, 4.4), 4.21-4.25 (m, 2H). 13C NMR (125 MHz, CDCl3): δ
-1.3, 17.3, 17.5, 49.2, 63.7, 68.4, 176.4. MS calcd [M + H]+
(C10H23O4Si): 235.1365. Found: (HRFAB) 235.1356. Anal.
Calcd for C10H22O4Si: C, 51.25; H, 9.46. Found: C, 51.33; H,
9.37.
(Ben zylid en e)4-[G-3]-COOH (3b). Compound 3a (1.6 g, 1.3
mmol) was dissolved in 40 mL of dry THF, and 2.5 mL of a 1
M tetrabutylammonium fluoride solution in THF was added.
The reaction mixture was stirred at room temperature for 1
h, then diluted with 100 mL of EtOAc, and washed with 1 M
NaHSO4 and then acidic brine. The organic phase was dried
and evaporated to give 1.4 g (91%) of 3b as a white glass. IR
1
(film from CH2Cl2): 3210, 1740. H NMR (500 MHz, CDCl3):
δ 0.92 (s, 12H), 1.02 (s, 3H), 1.19 (s, 6H), 3.58 (d, 8H, J ) 11.0),
4.04 (d, 2H, J ) 11.0), 4.12 (d, 2H, J ) 11.0), 4.28-4.38 (m,
8H), 4.57 (d, 8H, J ) 11.0), 5.40 (s, 4H), 7.28-7.30 (m, 12H),
7.39-7.44 (m, 8H). 13C NMR (125 MHz, CDCl3): δ 17.2, 17.8,
17.9, 42.7, 46.3, 46.9, 65.5, 66.3, 73.5, 101.9, 126.3, 128.3, 129.1,
137.7, 171.9, 173.25, 173.32. MS calcd [M + Na]+ (C63H74
-
NaO22): 1206.2. Found: (MALDI-TOF) 1206.3. Anal. Calcd for
C
63H74O22: C, 63.89; 6.30. Found: C, 64.05; H, 6.33.
N,N-Bis(2-cya n oeth yl)-eth a n ola m in e Meth oxym eth yl
Eth er (4b). The alcohol 4a (1.0 g, 6.0 mmol, 1.0 equiv) was
dissolved in THF (40 mL), and (iPr)2NEt (10 mL, 60 mmol, 10
equiv) was added. The solution was cooled to 0 °C, and then
distilled chloromethyl methyl ether (2.9 mL, 36 mmol, 6 equiv)
was added. The reaction mixture was stirred at 0 °C for 1 h
J . Org. Chem, Vol. 69, No. 1, 2004 51

Gillies and Fre´chet
) 5.7), 3.07 (t, 4H, J ) 6.3), 3.58 (dd, 8H, J ) 11.6, 3.5), 4.00-
4.13 (m, 6H), 4.32-4.37 (m, 8H), 4.54 (dd, 8H, J ) 11.6, 4.2),
4.64 (s, 2H), 5.32 (s, 2H), 5.40 (s, 4H), 7.29-7.32 (m, 12H),
7.37-7.39 (m, 8H). 13C NMR (125 MHz, CDCl3): δ 17.4, 17.78,
17.81, 27.7, 29.7, 36.6, 38.0, 42.6, 42.7, 46.6, 47.0, 50.6, 51.7,
51.9, 63.5, 65.3, 66.1, 73.6, 101.9, 126.3, 128.3, 129.1, 137.9,
158.04, 172.0, 172.3, 173.4. MS calcd [M + Na]+ (C93H123N5-
NaO24): 1717.9. Found: (MALDI-TOF) 1719.1. Anal. Calcd for
26.4, 28.4, 30.0, 40.2, 42.1, 42.2, 46.6, 46.9, 65.0, 65.5, 66.0,
66.1, 66.7, 98.1, 128.2, 128.3, 128.6, 135.6, 158.3, 171.2, 171.9,
172.1, 173.6. MS calcd [M + Na]+ (C63H96NaN2O25): 1304.4.
Found: (MALDI-TOF) 1305.2. Anal. Calcd for
C63H69-
NaN2O25: C, 59.05; H, 7.55; N, 2.19. Found: C, 59.33; H, 7.58;
N, 2.19.
(HO)8-[G-3]-glycin ylu r ea (12). Compound 11b (75 mg, 63
µmol, 1.0 equiv) was dissolved in 2 mL of CH3CN and was
diluted with 1 mL of 20 mM pH 7.0 borate buffer. CAN (5.5
mg, 10 µmol, 0.16 equiv) was added, and the reaction mixture
was heated at 50 °C for 2 h. After cooling the reaction mixture
was partitioned between THF and 0.1 M NaHSO4 in saturated
brine. The organic phase was washed with another portion of
the acidic brine, dried, and evaporated. The product was
purified by passing over a silica plug, using first EtOAc/MeOH
(90/10), followed by EtOAC/MeOH (80/20) to provide 55 mg
(85%) of 12 as a colorless glass. IR (film from THF): 3390,
C
93H123N5O24: C, 65.93; H, 7.31; N, 4.31. Found: C, 65.74; H,
7.27; N, 4.18.
N-(4-Nit r op h en yloxyca r b on yl)b en zyl Glycin a t e (8).
Benzyl glycinate (0.62 g, 3.8 mmol, 1.0 equiv), prepared as
previously reported29 was dissolved in 4 mL of 1:1 CH2Cl2/
pyridine and was added dropwise to a solution of 4-nitrophenyl
chloroformate (2.3 g, 11 mmol, 3 equiv) in 20 mL of CH2Cl2 at
0 °C. After 10 min, the solution was diluted with CH2Cl2 and
washed with 1 M NaHSO4 and brine. The organic phase was
evaporated, and the product was purified by column chroma-
tography using CH2Cl2/hexane (90/10) to elute with excess
4-nitrophenyl chloroformate, followed by CH2Cl2 to elute the
product. The fractions containing product were combined and
washed with 2% Na2CO3 to remove 4-nitrophenol. The organic
phase was dried and evaporated to provide 0.81 g (65%) of 8
as a white solid. Mp: 111-112 °C. IR (film from CH2Cl2):
3315, 3080, 1747, 1714, 1520. 1H NMR (500 MHz, CDCl3): 4.10
(d, 2H, J ) 6.2), 5.21 (s, 2H), 5.91 (t, 3H, J ) 5.6), 7.26-7.29
(m, 2H), 7.33-7.37 (m, 5H), 8.17-8.21 (m, 2H). 13C NMR (125
MHz, CDCl3): 43.0, 67.6, 122.1, 125.2, 128.5, 128.8, 128.8,
1
1735, 1726, 1584. H NMR (500 MHz, MeOD): 1.15 (s, 12H),
1.29 (s, 6H), 1.30 (s, 3H), 1.37-1.41 (m, 4H), 1.48-1.51 (m,
2H), 1.68-1.71 (m, 2H), 3.14 (t, 2H, J ) 7.0), 3.60 (d, 8H, J )
10.7), 3.68 (dd, 8H, J ) 10.9, 2.6), 3.72 (d, 2H, J ) 9.9), 4.16
(t, 2H, J ) 6.6), 4.23-4.33 (m, 12H). 13C NMR (125 MHz,
MeOD): 17.5, 18.3, 18.4, 27.0, 27.7, 29.8, 31.3, 41.2, 45.2, 48.1,
48.2, 51.9, 65.9, 66.3, 66.8, 67.5, 161.3, 173.9, 174.2, 176.1. MS
calcd [M + Na]+ (C44H74NaN2O25): 1054.1. Found: (MALDI-
TOF) 1053.9.
(HO)8-[G-3]-glycin ylu r ea Ben zyl Ester (13). The ester
11a (0.18 g, 0.14 mmol, 1.0 equiv) was dissolved in 2 mL of
CH3CN and was diluted with 1 mL of 20 mM pH 7.0 borate
buffer. CAN (12 mg, 22 µmol, 0.16 equiv) was added, and the
reaction mixture was heated at 50 °C for 2 h. After cooling,
the reaction mixture was partitioned between THF and
saturated brine. The organic phase was washed with another
portion of brine, dried, and evaporated. The product was
purified by passing it over a silica plug, using first EtOAc/
MeOH (90/10), followed by EtOAC/MeOH (80/20) to provide
0.13 g (85%) of 13 as a colorless glass. IR (film from THF):
135.1, 145.0, 153.4, 155.8, 169.5. MS calcd [M
+
H]+
(C16H15N2O6): 331.0930. Found: (HRFAB) 331.0936. Anal.
Calcd for C16H14N2O6: C, 58.21; H, 4.27; N, 8.49. Found: C,
58.48; H, 4.09; N, 8.66.
[3-(6-Hyd r oxyh exyl)u r eid o]a cetic Acid Ben zyl Ester
(9). To a solution of 8 (0.79 g, 2.4 mmol, 1.0 equiv) in 10 mL
of benzene were added 1,6-aminohexanol (0.34 g, 2.9 mmol,
1.2 equiv), DMAP (88 mg, 0.72 mmol, 0.30 equiv), and
diisopropylethylamine (0.46 g, 3.6 mmol, 1.5 equiv). The
reaction mixture was stirred at room temperature for 30 min,
diluted with 50 mL of CH2Cl2, and washed with 1 M NaHSO4,
2% Na2CO3, and saturated brine. The organic phase was dried
and evaporated to give 0.61 g (86%) of 9 as a white solid. Mp:
1
3400, 1737, 1660, 1572. H NMR (400 MHz, MeOD): 1.15 (s,
12H), 1.29 (s, 6H), 1.30 (s, 3H), 1.37-1.42 (m, 4H), 1.47-1.53
(m, 2H), 1.65-1.71 (m, 2H), 3.12-3.17 (m, 2H), 3.60 (d, 8H, J
) 10.9), 3.69 (dd, 8H, J ) 10.9, 2.1), 3.92 (s, 2H), 4.16 (t, 2H,
J ) 6.6), 4.25 (dd, 4H, J ) 11.0, 2.2), 4.29-4.34 (m, 8H), 5.17
(s, 2H), 7.31-7.39 (m, 5H). 13C NMR (100 MHz, MeOD): 17.5,
18.3, 18.4, 26.9, 27.6, 29.7, 31.2, 41.1, 43.0, 48.0, 51.9, 65.9,
66.3, 66.8, 67.4, 67.8, 129.35, 129.40, 129.7, 137.4, 161.1, 172.7,
173.9, 174.1, 176.0. MS calcd [M + Na]+ (C51H80NaN2O25):
1144.2. Found: (MALDI-TOF) 1144.7. Anal. Calcd for
1
75-77 °C. IR (film from CH2Cl2): 3350, 1740, 1648, 1580. H
NMR (500 MHz, CDCl3): 1.27-1.37 (m, 4H), 1.43-1.54 (m,
4H), 2.71 (s, 1H), 3.11-3.15 (m, 2H), 3.56-3.58 (m, 2H), 3.99
(d, 2H, J ) 6.0), 5.13 (s, 2H), 5.35 (t, 3H, J ) 5.5), 5.57 (t, 3H,
J ) 5.55), 7.29-7.35 (m, 5H). 13C NMR (125 MHz, CDCl3):
25.4, 26.5, 30.2, 32.6, 40.4, 42.4, 62.6, 67.1, 128.4, 128.6, 128.8,
135.5, 158.7, 171.7. MS calcd [M + H]+ (C16H25N2O4): 309.1814.
Found: (HRFAB) 309.1820. Anal. Calcd for C16H24N2O4: C,
62.34; H, 7.85; N, 9.08. Found: C, 62.12; H, 8.05; N, 9.08.
C
51H80N2O25: C, 54.63; H, 7.19; N, 2.50. Found: C, 54.46; H,
7.48; N, 2.44.
Oligo(eth ylen e oxid e)-[G-3]-gylcin ylu r ea Ben zyl Ester
(15a ). Compound 13 (79 mg, 70 µmol, 1.0 equiv) was dissolved
in 2 mL of DMF and was diluted with 4 mL of CH2Cl2. The
acid 14 (0.32 g, 1.1 mmol, 16 equiv), prepared as previously
reported,26 was added, followed by DCC (0.29 g, 1.4 mmol, 20
equiv), DMAP (28 mg, 0.23 mmol, 3.2 equiv), and DPTS (72
mg, 0.23 mmol, 3.2 equiv). The reaction mixture was stirred
at room temperature overnight under a nitrogen atmosphere
and then was filtered to remove DCU. The filtrate was diluted
with EtOAc and washed with saturated brine. The organic
phase was dried and evaporated. The resulting residue was
purified by column chromatography using a solvent gradient
from EtOAc/Hex (75/25) to CH2Cl2/MeOH (50/50), yielding 0.14
g (63%) of 15a as a colorless glass. IR (film from CH2Cl2): 3400,
1752, 1685, 1550. 1H NMR (400 MHz, CDCl3): δ 1.15 (s, 18H),
1.19 (s, 3H), 1.23-1.31 (m, 4H), 1.34-1.43 (m, 2H), 1.51-1.59
(m, 2H), 3.03 (m, 2H), 3.28 (s, 24H), 3.44-3.46 (m, 16H), 3.50-
3.56 (m, 48H), 3.60-3.66 (m, 20H), 3.90 (d, 2H, J ) 6), 4.02
(t, 2H, J ) 8.0), 4.14-4.22 (m, 72H), 5.05 (s, 2H), 5.25 (s, 1H),
5.40 (s, 1H), 7.24-7.28 (m, 5H). 13C NMR (100 MHz, CDCl3):
17.4, 17.7, 25.6, 26.3, 28.3, 30.1, 40.0, 42.0, 46.3, 46.5, 46.6,
58.9, 63.9, 65.2, 65.3, 65.5, 66.3, 66.5, 67.7, 67.8, 68.8, 70.42,
70.44, 71.8, 128.1, 128.2, 128.5, 135.5, 158.1, 169.2, 169.6,
(Isopr opyliden e)4-[G-3]-glycin ylu r ea Ben zyl Ester (11a).
The alcohol 9 (0.14 g, 0.48 mmol, 1.0 equiv) and acid 1024 (0.72
g, 0.72 mmol, 1.5 equiv) were dissolved in 10 mL of CH2Cl2.
DMAP (12 mg, 96 µmol, 0.20 equiv) and DPTS (30 mg, 96 µmol,
0.20 equiv) were added, followed by DCC (0.20 g, 0.96 mmol,
2.0 equiv), and the reaction mixture was stirred at room
temperature overnight under a nitrogen atmosphere. The
reaction was filtered to remove the dicyclohexylurea (DCU)
byproduct, and the filtrate was concentrated. The product was
purified by column chromatography using a solvent gradient
from EtOAc/Hex (60/40) to EtOAc/Hex (80/20) to afford 0.55 g
(91%) of 11a as a colorless glass. IR (film from CH2Cl2): 3400,
1753, 1686, 1656, 1562. 1H NMR (500 MHz, CDCl3): δ 1.12
(s, 12H), 1.27 (s, 3H), 1.28 (s, 6H), 1.34 (s, 12H), 1.34-1.38
(m, 4H), 1.41 (s, 12H), 1.45-1.49 (m, 2H), 1.60-1.67 (m, 2H),
3.17-3.21 (m, 2H), 3.62 (dd, 8H, J ) 11.8, 2.4), 4.00 (d, 2H, J
) 5.5), 4.11-4.16 (m, 10H), 4.20-4.34 (m, 12H), 5.14 (s, 2H),
5.35 (t, 1H, J ) 5.5), 5.51 (t, 1H, J ) 5.6), 7.30-7.36 (m, 5H).
13C NMR (125 MHz, CDCl3): 17.6, 17.7, 18.4, 21.6, 25.5, 25.7,
(29) Gray, C. J .; Quibell, M.; J iang, K.-L.; Baggett, N. Synthesis
1991, 2, 141-147.
52 J . Org. Chem., Vol. 69, No. 1, 2004

Self-Assembly of Dendritic Bow-Ties
171.2, 171.3, 171.5, 171.9. MS calcd [M + Na]+ (C139H224
NaN2O81): 3242.3. Found: (MALDI-TOF) 3242.9. Anal. Calcd
for C139H224N2O81: C, 51.86; H, 7.01; N, 0.87. Found: C, 51.67;
H, 6.91; N, 0.89.
-
Squibb as a Sponsoring Member and Novartis Pharma
as Supporting Member. We thank the National Institute
of Health (GM 65361 and EB 002047) and the U.S.
Department of Energy (DE-AC03-765F00098) for sup-
port of this research.
Gen er a l P r oced u r e for Com p lex F or m a tion a n d De-
ter m in a tion of Associa tion Con sta n ts by 1H NMR. Com-
plexes were formed by combining the complementary amine
and acid in a 1:1 molar ratio in dry CDCl3. Association
Su p p or tin g In for m a tion Ava ila ble: General experimen-
tal procedures and materials; procedures for preparation of
compounds 2a , 2b, 3a , 4a , 7, 11b, and 15b; and 1H NMR
spectrum of compound 12. This material is available free of
charge via the Internet at http://pubs.acs.org.
1
constants were determined by H NMR at 500 MHz in CDCl3
using the dilution protocol27 over a concentration range from
∼60 to ∼ 0.2 mM.
Ack n ow led gm en t. The Center for New Directions
in Organic Synthesis is supported by Bristol-Myers
J O035329S
J . Org. Chem, Vol. 69, No. 1, 2004 53