Fast and convenient divergent synthesis of aliphatic ester dendrimers by anhydride coupling

Article abstract of DOI:10.1021/ja010524e

A novel divergent approach was developed for the synthesis of dendritic aliphatic polyester structures using an acetal-protected anhydride derivative of 2,2-bis(hydroxymethyl)propionic acid as the acylating agent. This divergent synthesis is remarkable, b

Full text of DOI:10.1021/ja010524e

5908
J. Am. Chem. Soc. 2001, 123, 5908-5917
Fast and Convenient Divergent Synthesis of Aliphatic Ester
Dendrimers by Anhydride Coupling
Henrik Ihre, Omayra L. Padilla De Jesu´s, and Jean M. J. Fre´chet*
Contribution from the Center for New Directions in Organic Synthesis, Department of Chemistry,
UniVersity of California, Berkeley, California 94720-1460
ReceiVed February 26, 2001
Abstract: A novel divergent approach was developed for the synthesis of dendritic aliphatic polyester structures
using an acetal-protected anhydride derivative of 2,2-bis(hydroxymethyl)propionic acid as the acylating agent.
This divergent synthesis is remarkable, because unlike all others, it only requires a small excess of reagent to
achieve quantitative growth, and it requires no means of purification other than a simple solvent extraction or
precipitation. A monodisperse sixth generation dendrimer with molecular weight of 30 711 Dalton and 192
masked hydroxyl groups was prepared in high yield and purity using 1,1,1-tris(hydroxyphenyl)ethane as the
core molecule. Linear and star-shaped poly(ethylene glycol) (PEG) derivatives of narrow polydispersity were
also used as core molecules in the divergent synthesis of dendritic-linear copolymer hybrids up to the fourth
generation without requiring any chromatographic purification.
Introduction
Two different synthetic strategies are employed to construct
regular dendritic frameworks. The first is the divergent approach
introduced independently by Tomalia6 and Newkome7 in their
synthesis of PAMAM and arborol dendrimers; the second is
the convergent approach of Hawker and Fre´chet.8 The two
approaches complement each other and neither is generally
better. The choice of synthetic approach is usually justified by
the features of the target molecule, the chemistry available for
growth, and the specific building blocks used in the construction
of the dendritic framework. The convergent approach is gener-
ally acknowledged to provide better overall structural control,
in part as a result of its enhanced potential for purification at
intermediate stages of the synthesis, and in part as a result of
its innate ability to introduce differentiated functionalities at the
focal point and the periphery of the dendrimer. In the divergent
approach, structural uniformity is harder to maintain, because
the number of reactions that must be completed at each step of
growth increases exponentially, thus requiring large excesses
of reagents, but the process is better suited not only for syntheses
Over the past decade, chemists have developed a large number
of synthetic routes to a variety of dendritic macromolecules
using different chemistries and monomers.1 The ability to
precisely control the three-dimensional structure, functionality,
and material properties of a molecule has always been a
challenge for chemists. Today, most of the well-defined
macromolecules in existence are still supplied by nature itself.
Dendrimers represent one of the very few families of synthetic
macromolecules that possess a structural precision approaching
that of proteins. As a result of their structural precision, globular
shape, and high functionality, dendrimers have found use in a
large number of applications that are frequently inspired from
natural systems. For instance, dendrimers have demonstrated
unique properties that enable their use in molecular encapsula-
tion,2 light-harvesting systems,3 biomedical applications4 and
catalysis.5 However, the synthetic procedures used for their
preparation involve multiple steps with intermediate purifications
that detract from their widespread use.
* To whom correspondence should be addressed. Phone: (510) 643-
3077. Fax: (510) 643-3079. Email: frechet@cchem.berkeley.edu.
(1) (a) G. R. Newkome, G. R. Moorefield, C. N. F. Vo¨gtle, F. Dendritic
Molecules: Concepts, Synthesis, PerspectiVes, VCH: Weinheim, 1996. For
recent reviews consult: (b) Bosman, A. W.; Jansen, H. M.; Meijer, E. W.;
Chem. ReV. 1999, 99, 1665. (c) Fischer, M.; Vo¨gtle, F. Angew. Chem., Int.
Ed. Engl. 1999, 38, 885. (d) Majoral, J.-P.; Caminade, A.-M. Chem. ReV.
1999, 99, 845. (e) Matthews, O. A.; Shipway, A. N.; Stoddart, J. F. Prog.
Polym. Sci. 1998, 23, 1. (f) Frey, H.; Lach, C.; Lorenz, K.; AdV. Mater.
1998, 10, 279. (g) Fre´chet, J. M. J.; Hawker C. J. In ComprehensiVe Polymer
Science;Aggarwal, S. L., S. Russo, S., Eds.; 2nd supplement; Pergamon:
Oxford, 1996, p 140.
(2) (a) For a review, see: Hecht, S.; Fre´chet, J. M. J. Angew. Chem.,
Int. Ed. 2001, 40, 74. (b) Hawker, C. J.; Wooley, K. L.; Fre´chet, J. M. J.
J. Am. Chem. Soc. 1993, 115, 4375. (c) Jin, R.-H.; Aida, T.; Inoue S. J.
Chem. Soc., Chem. Commun. 1993, 1260. (d) Kawa, M.; Fre´chet, J. M. J.
Chem. Mater. 1998, 10, 286-296. (e) Jiang, D.-L.; Aida, T. Nature 1997,
388, 454-456. (f) Pollak, K. W.; Leon, J. W.; Fre´chet, J. M. J.; Maskus,
M.; Abrun˜a, H. D. Chem. Mater. 1998, 10, 30.
(4) (a) Haensler, J.; Szoka, F. C. Bioconjugate Chem. 1993, 4, 372. (b)
Tang, M. X.; Szoka, F. C. Gene Ther. 1997, 4, 823. (c) Tang, M. X.;
Redemann, C. T.; Szoka, F. C. Bioconjugate Chem. 1996, 7, 703. (d) Malik,
N.; Wiwattanapatapee, R.; Klopsch, R.; Lorenz, K.; Frey, H.; Weener, J.
W.; Meijer, E. W.; Paulus, W.; Duncan, R. J. Cont. Relat. 2000, 65, 133.
(e) Liu, M. J.; Fre´chet. J. M. J. Pharm. Sci. Technol. Today 1999, 2, 393.
(5) (a) Knapen, J. W. J.; van der Made, A. W.; de Wilde, J. C.; van
Leeuwen, A. W.; Wijkens, P.; Grove, D. M.; van Koten, G. Nature 1994,
372, 659. (b) Piotti, M. E.; Rivera, F.; Bond, R.; Hawker, C. J.; Fre´chet, J.
M. J. J. Am. Chem. Soc. 1999, 121, 9471. (c) Albrecht, M.; Gossage, R.
A.; Lutz, M.; Spek, A. L.; van Koten, G. Chem. Eur. J. 2000, 6, 1431. (d)
Brunner, H. J. Organomet. Chem. 1995, 500, 39. (e) Bolm, C.; Derrien,
N.; Seger, A. Synlett 1996, 387. (f) Yamago, S.; Furukuwa, M.; Azuma,
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C. C. J. Org. Chem. 1997, 62, 5116. (h) Oosterom, G. E.; van Haaren, R.
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Commun. 1999, 1119.
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J. R.; Ryder, J.; Smith, P. Polym. J. 1985, 17, 117.
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Chem. 1985, 50, 2003.
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10.1021/ja010524e CCC: $20.00 © 2001 American Chemical Society
Published on Web 06/02/2001

Aliphatic Ester Dendrimer Synthesis
J. Am. Chem. Soc., Vol. 123, No. 25, 2001 5909
Scheme 1
on a larger scale but also for the preparation of high-generation
dendrimers.
the hydroxyl-terminated polyester dendrons was eventually
achieved with a double-stage convergent approach using ac-
etonide-protected building blocks and N,N′-dicyclohexylcarbo-
diimide (DCC) for the coupling steps.12 Once deprotected, the
hydroxyl-functionalized dendrons can easily undergo “surface”
functionalization in reactions, such as the growth of ꢀ-capro-
lactone via controlled ring-opening polymerization to afford
dendritic star structures.13
Given the compact nature of the building block and the
specific chemistry used in these synthetic routes, the main
drawbacks of these syntheses rest in the repeated purifications
by column chromatography and the increased steric inhibition
to growth that are observed at higher generations. In addition,
one implementation of our drug delivery target application
requires that the polyfunctional drug be attached in a last
synthetic step to the periphery of the fully constituted dendritic
carrier; therefore, a new synthetic route alleviating these
problems was developed. It involves a divergent growth based
on a novel anhydride derivative of 2,2-bis(hydroxymethyl)-
propionic acid 2.
As part of a program in targeted drug delivery,9 we have been
interested in the development of biocompatible aliphatic den-
drimers lacking the toxicity10 associated with the two com-
mercial families of amine-containing dendrimers. Here, we
present a divergent synthesis of aliphatic ester dendrimers by
anhydride coupling, based on readily available 2,2-bis(hy-
droxymethyl)propionic acid as the repeating unit. Using this
approach, the sixth generation benzylidene-protected dendrimer
with a molecular weight of 30 711 was obtained in high yields
and purity. Linear and star-shaped poly(ethylene glycol) (PEG)
of narrow polydispersity (PDI ∼ 1.03) were also used as cores
for the divergent growth of novel linear-dendritic hybrids. This
novel route is noteworthy for its rapidity and ability to rapidly
produce high-generation aliphatic ester dendrimers of high purity
with no means of purification other than solvent extraction and
precipitation.
Results and Discussion
The building block used as the acylating agent in this
divergent synthesis is the benzylidene-protected anhydride
derivative 2 of 2,2-bis(hydroxymethyl)propionic acid. The
preparation of 2, shown in Scheme 1, starts with the protection
of the diol group of 2,2-bis(hydroxymethyl)propionic acid by
reaction with benzaldehyde dimethyl acetal and a catalytic
amount of p-toluenesulfonic acid (TsOH) in dry acetone to
afford 1. Although benzaldehyde itself can be used for this
reaction, use of its dimethyl acetal derivatives provides for easier
workup and higher yields of 1. Anhydride 2 is then obtained
by self-condensation of 1 in CH2Cl2 using N,N′-dicyclohexyl-
carbodiimide (DCC) as the dehydrating agent. DCC provides
mild, rapid, and high-yielding access to the symmetrical
anhydride, but other reagents, such as P2O5 or acetic anhydride,
are more difficult to use given the presence of acid-labile acetal
protective groups. The crude anhydride 2 is easily purified from
remaining N,N′-dicyclohexylurea (DCU) and excess DCC by
Synthesis of Polyether Dendrimers from a Tris-Phenolic
Core. In previous work, acetate-terminated polyester dendrons
based on 2,2-bis(hydroxymethyl)propionic acid ranging from
generations one to four were synthesized according to a strictly
convergent growth approach;11 however, the original design
suffered from a lack of versatility, because the desirable
deprotection of the terminal acetate groups to obtain the
corresponding hydroxyl-terminated dendrimers could not be
achieved without some concomitant cleavage of the dendrimer
itself. In addition, coupling of the fourth generation dendrons
to the core molecule could only be achieved in a yield
significantly lower than that obtained in the coupling steps that
were used to prepare the lower generation dendrons. Access to
(9) (a) Liu, M.; Kono, K.; Fre´chet, J. M. J. J. Polym. Sci., Polym. Chem.
1999, 37, 3492. (b) Kono, K.; Liu, M.; Fre´chet, J. M. J. Bioconjugate Chem.
1999, 10, 1115. (c) Grayson, S. M.; Jayaraman, M.; Fre´chet, J. M. J. Chem.
Commun. 1999, 1329. (d) Liu, M.; Kono, K.; Fre´chet, J. M. J. J. Controlled
Release 2000, 65, 121.
(10) Malik, N.; Wiwattanapatapee, R.; Klopsch, R.; Lorentz, K.; Frey,
H.; Weener, J. W.; Meijer, E. W.; Paulus, W.; Duncan, R. J. Control. Relat.
2000, 65, 133.
(12) Ihre, H.; Hult, A.; Fre´chet, J. M. J.; Gitsov, I. Macromolecules 1998,
31, 4061.
(13) Trollsås, M.; Hedrick, J. L.; Mecerreyes, D.; Dubois, Ph.; Je´roˆme,
R.; Ihre, H.; Hult, A. Macromolecules 1997, 30, 8508.
(11) Ihre, H.; So¨derlind, E.; Hult, A. J. Am. Chem. Soc. 1996, 118, 6388.

5910 J. Am. Chem. Soc., Vol. 123, No. 25, 2001
Ihre et al.
Scheme 2
precipitation of the CH2Cl2 solution into hexane under vigorous
stirring to afford an essentially pure product.
solved in CH2Cl2 and evaporated to afford a high-purity
benzylidene-protected dendrimer as a glass.
Coupling of 2 with the triphenolic core molecule 1,1,1-tris-
(hydroxyphenyl)ethane is readily accomplished using only 1.25
equivs of 2/hydroxyl group to afford a 94% isolated yield of 3.
The esterification reaction is best performed in a 1:3 mixture
of pyridine and CH2Cl2 at a concentration of ∼0.3 M using
20-25 mol % of DMAP as the acylating catalyst. Attempts to
perform the esterifications either without DMAP or in a very
dilute solution resulted in low conversions and long reaction
times. Other solvents such as THF, DMF, and MeCN are also
suitable as solvents in the formation of dendritic aliphatic esters
using anhydride 2 as the acylating agent; however, because
higher generation hydroxyl functional dendrimers are sparingly
soluble in these solvents, it was found most efficient to
predissolve the hydroxyl-functional dendrimer in pyridine and
then dilute the reaction mixture with a solvent such as CH2Cl2.
After stirring at room temperature for 3 h, the excess of the
anhydride 2 was quenched by stirring the reaction mixture with
a solution (1:1) of pyridine and water overnight. The reaction
mixture was then diluted with CH2Cl2 and extracted with
NaHSO4 (1 M), then Na2CO3 (10% w/v), and finally, with brine
to remove pyridine, DMAP, and the benzylidene-protected acid
1 that is formed as a byproduct. The reaction is so clean that
the product obtained after this simple workup is essentially pure.
As will be seen below, the next step of the synthesis involves
a Pd catalyst for the removal of the benzylidene protecting
groups. It is, therefore, essential to ensure that all of the pyridine
and DMAP are removed from the dendrimers in the extraction
and washing steps to avoid catalyst deactivation.
The benzylidene protecting groups of 3 and larger dendrimers
such as the fourth generation dendrimer 9 (Scheme 2) can be
selectively removed in very high yields by catalytic hydro-
genolysis in a process that does not affect the ester bonds of
the dendritic backbone. Hydrogenolysis is best carried out by
stirring overnight under medium pressure of H2 using 10% w/w
of Pd/C (10%) as catalyst; therefore, deprotection of 3 affords
the corresponding first generation hydroxyl-functional dendrimer
4 in 97% yield, and deprotection of 9 affords dendrimer 10 with
48 peripheral hydroxyls in 95% yield after purification by
precipitation. The deprotection reaction is easily monitored by
1H NMR spectroscopy using DMSO-d6 as solvent, and the pure
product is isolated almost quantitatively after removal of the
catalyst by filtration. Removal of the protecting groups by
hydrogenolysis was preferred over alternate routes involving
hydrolysis, because the latter required very long reaction times
and the use of more difficult workup procedures.
Using this iterative divergent growth process, the sixth
generation benzylidene-functional dendrimer with a molecular
weight of 30 711 and 192 masked terminal hydroxyl groups
was obtained in high yields and purity using no means of
purification other than extraction and precipitation. The process
is noteworthy, because it is unlike all other divergent syntheses
that require a large excess of reagent to be used in the growth
steps. Here, only a small excess of the anhydride (at most, 1.25
equivs of 2/hydroxyl group) is needed to drive each growth step
to completion, even at high generation. Both the quantitative
nature of the coupling reaction and the fact that the only side
product formed is the benzylidene-protected acid 1 greatly
facilitate product isolation after a trivial workup procedure.
We also explored the alternate approach involving the direct
DCC coupling of acid 1 rather than anhydride 2 using either
4-(dimethylamino)pyridine (DMAP) or 4-(dimethylamino)-
pyridinium p-toluenesulfonate (DPTS)14 as the acylation catalyst
for the preparation of higher generation dendrimers. This
approach led to product mixtures, including partially acylated
molecules, that proved very difficult to purify by column
chromatography. In addition, because a large excess of reagent
To prepare larger dendrimers, the sequence of the anhydride
coupling step and the subsequent deprotection by hydrogenolysis
is repeated until a dendrimer of the desired size is obtained.
The extractive workup procedure described above is fully
satisfactory for the first three generations of polyester dendrim-
ers. At higher generations, a small amount of DCU present in
the anhydride 2 accumulates in the system and can be detected
1
both by H NMR spectroscopy and by size exclusion chroma-
tography (SEC); therefore, the extraction procedure is comple-
mented by an additional step of precipitation of the crude
benzylidene functional dendrimers from a CH2Cl2 solution into
hexane under vigorous stirring. The precipitate is then redis-
(14) Moore, J. S.; Stupp, S. I. Macromolecules 1990, 23, 65.

Aliphatic Ester Dendrimer Synthesis
J. Am. Chem. Soc., Vol. 123, No. 25, 2001 5911
Scheme 3
had to be used at higher generations in order to attempt complete
coupling, significant amounts of the rearranged N-acylurea
byproduct were formed.
respect to the anhydride) predissolved in CH2Cl2 at a concentra-
tion of 10-40 mM was treated with an excess of anhydride 2
added as the neat reagent. In view of the dilution effect caused
by the presence of the large PEG moiety, the use of an excess
of 2 larger than the 1.25-fold excess used earlier is desirable to
avoid excessively long reaction times; typically, 2-4 equivs of
2 may be used. After stirring at room temperature for 5-18 h,
the excess of anhydride was quenched with methanol. Because
both side-products, the benzylidene protected acid and its methyl
ester formed during the coupling and quenching reactions, are
readily soluble in diethyl ether, but the PEG hybrids are not,
purification is readily accomplished by precipitation of the
reaction mixture into diethyl ether. The quenching procedure
is necessary, because anhydride 2 is insoluble in ether, and it
would contaminate the precipitated PEG hybrids isolated by
precipitation in that solvent. After filtration and washing with
diethyl ether, the highly pure dendritic hybrids are isolated as
white powders in yields of >90%. Once again, removal of the
benzylidene protecting groups was achieved by catalytic hy-
drogenolysis and the alcohol-terminated hybrids were isolated
in near quantitative yield by precipitation in ether.
Preparation of Dendritic Linear Hybrids. The versatility
and simple experimental implementation of this novel and
extremely efficient divergent approach to dendritic aliphatic ester
structures was further demonstrated by syntheses in which the
dendrons were built from the chain-ends of narrow polydisper-
sity linear and star-shaped poly(ethylene glycols) (PEGs) used
as core molecules (Scheme 3). Dendritic PEG hybrids have been
prepared previously using both convergent and divergent
growth.13 These hybrids have interesting properties as a result
of the intrinsic differences that exist between the core and
dendritic portions of the molecules, leading to amphiphilic
properties and to their use as surface modifiers,16 “stimulus-
responsive” materials,17 and drug carriers,18 for instance.
The specific features of our target polyester-PEG structure
are fully compatible with the divergent growth approach,
because the PEG core may be used to assist in product
purification through simple precipitation, but the terminal
functionalities of the dendritic-linear hybrid remain available
for the direct attachment of a functional molecule, such as a
drug or a chromophore.
Three different low-polydispersity (PDI ∼ 1.03) PEGs were
used as starting materials to prepare the dendritic PEG hy-
brids: a linear monomethyl ether PEG alcohol (5500 Da), a
linear telechelic PEG diol (10 604 Da), and a four-arm star PEG
tetraol (20 330 Da). After growth of fourth generation dendrons
from their terminal hydroxyl groups, these should afford hybrid
molecules displaying a total of 16, 32, and 64 benzylidene
acetal-protected hydroxyl groups, respectively, at their surfaces
(Figure 1). Once again, the preparation procedure that was used
is very simple and amenable to operation on a rather large scale.
The hydroxyl-functional PEG and DMAP (20 mol % with
General Characterization. The techniques that were used
for the characterization of the various dendrimers were 1H NMR,
13C NMR, size exclusion chromatography (SEC), and MALDI-
TOF; however, the characterization of especially high-generation
dendrimers may be somewhat troublesome, as pointed out in a
1
recent review.19 Examination of the H NMR spectra reveals
unique generation-related features, such as the methyl resonance
of the building block that shifts downfield for the successive
generational layers, most clearly for the low-generation numbers.
As expected, all of these methyl resonances are seen as singlets,
but of significantly different chemical shifts reflecting the
generation: from 1.21 for the benzylidene-protected G-1 to 0.79
1
for G-6. In addition, H NMR spectroscopy proved invaluable
for monitoring the removal of the benzylidene protective groups,
because thin-layer chromatography is ineffective for the dif-
ferentiation of fully and partial deprotected species because of
the very small differences in Rf values expected for closely
related molecules with large numbers of reaction sites. For the
(15) (a) Kim, Y. H.; Webster, O. Macromolecules 1992, 25, 5561. (b)
Warakomski, J. M. Chem. Mater. 1992, 4, 1000. (c) Gitsov, I.; Wooley, K.
L.; Fre´chet, J. M. J. Angew. Chem., Int. Ed. Engl. 1992, 31, 1200. (d) Gitsov,
I.; Fre´chet, J. M. J. Macromolecules 1993, 26, 6536.
(16) Fre´chet, J. M. J.; Gitsov, I.; Monteil, T.; Rochat, S.; Sassi, J. F.;
Vergelati, C.; Yu, D. Chem. Mater. 1999, 11, 1267.
(17) Gitsov, I.; Fre´chet, J. M. J. J. Am. Chem. Soc. 1996, 118, 3785.
(18) Liu, M.; Kono, K.; Fre´chet, J. M. J. J. Polym Sci A: Polym Chem
1999, 37, 3492.
(19) Bosman, A. W.; Janssen, H. M.; Meijer, E. W. Chem. ReV. 1999,
99, 1665.

5912 J. Am. Chem. Soc., Vol. 123, No. 25, 2001
Ihre et al.
Figure 1. Three types of hybrids of PEG and [G-4] polyester dendrons obtained from PEGs with one, two, or four reactive ends.
sixth generation polyester dendrimer, the symmetry of the two
doublets emanating from the core molecule at 7.05-7.14 ppm
suggests a fully substituted core molecule. In contrast, reso-
nances between 6.6 and 6.8 ppm would indicate a partly
substituted core molecule. As expected, the molecular weights
determined by SEC for these polymeric systems were not in
agreement with those calculated using calibration with linear
polystyrene. This phenomenon, which is related mainly to the
highly globular shape adopted by these very compact dendrim-
ers, has been observed previously in our work with polyether
dendrimers for a comparable range of generations;20 therefore,
the fifth generation dendrimer 11, with a theoretical molecular
weight of 15 334 Dalton shows a polystyrene-equivalent mo-
lecular weight of only 6012 by SEC (Figure 2). MALDI-
TOFMS analysis proved invaluable in confirming that complete
reaction of all peripheral groups was achieved during early
generation growth. In the synthesis of dendrimers of higher
generations, SEC analysis showed polydispersity values
(Mw/Mn) below those of the linear polystyrene standards used
for column calibration, and MALDI-TOFMS analysis was used
effectively to monitor coupling, because the technique is capable
of detecting instances of incomplete reactions during the
formation of the next higher generation. In a kinetic study,
MALDI-TOF analysis was used to monitor the formation of
the fifth generation dendrimer 11, prepared from the fourth
generation dendrimer with 48 reactive hydroxyl groups (Figure
3). Although the reaction was complete after 7 h of reaction
time, there was no observable trace of any product having
undergone less than 44 of the possible 48 coupling reactions
even after only 1 h of reaction. This finding is somewhat
surprising, considering the large number of reactive sites and
the steric implications resulting from the very compact nature
Figure 2. SEC trace of the fifth generation benzylidene-terminated
dendrimer with Mn (theory) ) 15 334 Da and Mn (SEC) ) 6012 Da.
of the dendrimers. It is clear that the kinetics of this reaction
are significantly faster than those for the single ether-forming
divergent growth step of the synthesis we developed 10 years
ago to prepare very large polyether dendrimers via a double-
stage growth method.21 In this earlier instance, we had also
noticed a scarcity of partially reacted molecules while starting
material and near-fully reacted products coexisted.
Although SEC analysis is clearly extremely valuable, its
resolution limits are such that it is not possible to distinguish
between fully and near-fully reacted dendrimers during genera-
tion growth. For example, SEC analysis of the sample obtained
after 1 h of reaction time during growth of the fifth generation
dendrimer shows a single peak with a polydispersity index of
1.008, confirming that SEC is not the optimal technique for
(20) (a) Hawker, C. J.; Fre´chet, J. M. J. J. Am. Chem. Soc. 1990, 112,
7638. (b) Mourey, T. H.; Turner, S. R.; Rubinstein, M.; Fre´chet, J. M. J.;
Hawker, C. J.; Wooley, K. L. Macromolecules. 1992, 25, 2401.
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1991, 113, 4252.

Aliphatic Ester Dendrimer Synthesis
J. Am. Chem. Soc., Vol. 123, No. 25, 2001 5913
Figure 3. MALDI-TOFMS trace for the formation of the fifth
generation dendrimer 11 with a theoretical molecular weight of 15 334
Da after 1, 2, and 7 h.
Figure 5. MALDI-TOFMS traces showing the generational increment
for the telechelic PEGs in hybrids with benzylidene-protected [G-n]
dendrons (n ) 1-4).
Conclusion
A novel, very simple, and highly efficient divergent approach
for the synthesis of aliphatic polyester dendrimers based on
anhydride coupling has been developed and shown to be
successful with a variety of cores. A monodispersed [G-6]
polyester tridendron dendrimer with a molecular weight of
30 711 Dalton was synthesized as well as three different families
of PEG-[G-4] polyester dendron hybrids. In all cases, the only
purification that was used involved extraction and precipitation,
thus affording very high purity materials. The simplicity and
experimental ease of this novel divergent route to aliphatic ester
dendrimers make it extremely attractive for the preparation of
high-generation dendrimers at a reasonable cost. We are
currently exploiting several families of dendrimers derived from
this chemistry for applications in the fields of catalysis5b and
polymer therapeutics.9,10
Figure 4. MALDI-TOFMS trace of the sixth generation dendrimer
13 with a theoretical molecular weight of 30 711 Da.
validating the purity of high-generation dendrimers. For the sixth
generation dendrimer with a molecular weight of 30 711 Dalton,
slight peak broadening was observed in the MALDI spectrum
(Figure 4), but the data suggests that even at such high
generation, full coupling was achieved within the detection limits
of our instrumentation.
Experimental Section
General Procedures. All chemicals were purchased from Aldrich
and used without any further purification. Solvents (Fischer) were
The PEG-polyester dendron hybrids were characterized using
both 1H NMR and MALDI-TOFMS. In the 1H NMR spectrum,
the integration of signals corresponding to the single benzylic
and aromatic protons at ∼5.5 ppm and ∼7.0-7.5 ppm,
respectively, can be compared with those between 0.8 and 1.5
ppm, corresponding to the isolated methyl groups of the building
blocks that are characteristic of each generation. Any defect on
the dendron resulting from incomplete coupling reactions would
be observed near the methyl (0.8-1.5 ppm) and methylene
(∼4.5 ppm) resonances of the building block, within the limits
of detection of the NMR technique. Because of the intrinsic
polydispersity of the PEG used for these hybrids, the SEC peaks
are broader than for the pure dendrimers; however, as reported
previously for analogous dendritic-linear hybrids,22 MALDI-
TOF provides invaluable data for the characterization of these
macromolecules and suggests that dendrimer growth is highly
regular (Figure 5).
1
reagent grade (99.9%). H and 13C NMR spectra were recorded on a
Bruker AMX 300, AM 400, or DRX 500, as specified. The solvents
used were CDCl3 and DMSO-d6. The solvent signals were used as
1
internal standards for both H NMR and 13C NMR recordings. Size-
exclusion chromatography (SEC) with double detection was performed
at 45 °C on a chromatography line calibrated with linear polystyrene
standards and fitted with with three 7-µm ultra-Styragel columns having
pore sizes 100 and 500 Å and a linear column, a differential refractive
index (DRI) detector M410, and a photodiode array (PDA) detector
M991 (Waters). THF was used as eluent at a nominal flow of 1 mL/
min. Corrections for the flow rate fluctuation were made by using
toluene as an internal standard. For compounds having a molecular
mass <1000 Da and all polyol dendritic species, mass spectral data
was collected by a Micromass LC-TOF instrument in positive mode.
For benzylidene protected dendrimers, MALDI-TOFMS data was
collected on a PerSeptive Biosystems Voyager-DE instrument in
positive ion mode using a 9-nitroanthracene matrix with silver
trifluoroacetate and calibration against bovine insulin standards. For
PEG-polyester dendron hybrids, the matrix used was R-cyano-4-
hydroxycinnamic acid, and no silver trifluoroacetate was used. M-H-W
Laboratories (Phoenix, AZ) performed the elemental analyses.
Although it must be emphasized that NMR and, to a lesser
extent, MALDI-TOF suffer from resolution limitations that
would preclude the detection of very low levels of impurities
if such were present, it is clear that the coupling and deprotection
that we report proceed in remarkably high conversions, leading
to rather pure products.
Preparation of Benzylidene-2,2-bis(oxymethyl)propionic Acid (1).
2,2-Bis(hydroxymethyl)-propionic acid 20.00 g (149 mmol), 34.04 g
(222 mmol) benzaldehyde dimethyl acetal, and 1.42 g (7.4 mmol)
p-toluenesulfonic acid monohydrate (TsOH) were mixed in 150 mL
of acetone. The reaction mixture was stirred for 4 h at room temperature.
After storage of the reaction mixture in the refrigerator overnight, the
(22) Yu, D.; Vladimirov, N.; Fre´chet, J. M. J. Macromolecules 1999,
32, 5186.

5914 J. Am. Chem. Soc., Vol. 123, No. 25, 2001
Ihre et al.
solids were filtered off and washed with cold acetone to give 1 as white
crystals: 21.0 g, (64%). IR (cm-1, thin film from CHCl3): 3400-
CDCl3): δ 0.98 (s, 18), 1.42 (s, 9), 1.97 (s, 3), 3.63 (d, 12, J ) 11.5),
4.52 (s, 12), 4.63 (d, 12, J ) 11.5), 5.43 (s, 6), 6.80 (d, 6, J ) 8.9),
6.88 (d, 6, J ) 8.9), 7.25 (m, 18), 7.39 (m, 12). 13C NMR (500 MHz,
CDCl3): δ 17.72, 17.17, 42.65, 47.06, 51.39, 65.60, 73.42, 73.49,
101.77, 120.76, 126.11, 128.08, 128.83, 129.55, 137.62, 146.11, 148.45,
171.41, 173.29. Calcd.: [M]+ m/z ) 1880.06. Found: MALDI-TOF:
[M + Ag]+ ) 1984. Anal. Calcd for C107H114O30: C, 68.36; H, 6.11.
Found: C, 68.39; H, 6.26.
1
2300 (br), 1699 (s). H NMR (500 MHz, CDCl3): δ 1.11 (s, 3), 3.70
(d, 2, J ) 11.7), 4.63 (d, 2, J ) 11.4), 5.49 (s, 1), 7.37 (m, 3), 7.48 (m,
2). 13C NMR (500 MHz, CDCl3): δ 17.58, 41.58, 72.65, 100.37, 126.10,
128.01, 128.70, 138.39, 175.58. Calcd.: [M]+ m/z ) 222.24. Found:
TOFMS-ES: [M + Na]+ ) 245.10. Anal. Calcd for C12H14O4: C,
64.85; H, 6.35; O, 28.80. Found: C, 64.89; H, 6.52.
[G-2]-(OH)12 (6). [G-2]-(O2Bn)6 (5) (778 mg, 410 µmol) was
dissolved in 20 mL of CH2Cl2 and diluted with 20 mL of methanol. 50
mg Pd/C (10%) was added to the solution. The procedure described
above was repeated to give 6 as a white glass: 544 mg, (97%). IR
(cm-1, thin film from THF): 3416 (br), 1734 (s). 1H NMR (500 MHz,
DMSO-d6): δ 1.09 (s, 18), 1.33 (s, 9), 2.17 (s, 3), 3.44 (d, 12, J )
8.5), 3.50 (d, 12, J ) 10.5), 4.26 (dd, 12, J ) 22.8, 10.5), 7.11 (m,
12). 13C NMR (500 MHz, DMSO-d6): δ 16.83, 17.16, 46.73, 50.49,
51.35, 63.87, 65.17, 121.28, 129.40, 146.21, 148.55, 171.50, 174.23.
Preparation of Benzylidene-2,2-bis(oxymethyl)propionic Anhy-
dride (2). Compound 1 (20.00 g, 90 mmol) and 10.21 g (49.5 mmol)
of N,N′-dicyclohexylcarbodiimide (DCC) were mixed in 150 mL of
CH2Cl2. The reaction mixture was stirred overnight at room temperature.
The precipitated urea DCC byproduct was filtered off in a glass filter
and washed with a small volume of CH2Cl2. The crude product was
purified by precipitating the filtrate into 1000 mL of hexane under
vigorous stirring. After filtration, 2 was isolated as white crystals: 17.1
g (89%). IR (cm-1, thin film from CHCl3): 3050, 1814 (s), 1746 (s).
1H NMR (300 MHz, CDCl3): δ 1.12 (s, 6), 3.69 (d, 4, J ) 10.5), 4.66
(d, 4, J ) 10.5), 5.47 (s, 2), 7.35 (m, 6), 7.45 (m, 4). 13C NMR (400
MHz, CDCl3): δ 16.85, 44.18, 73.17, 102.11, 126.27, 128.22, 129.09,
137.56, 169.12. Calcd.: [M]+ m/z ) 426.46. Found: TOFMS-ES: [M
+ Na]+ ) 449.20. Anal. Calcd for C24H26O7: C, 67.59; H, 6.15.
Found: C, 67.37; H, 6.30.
Calcd.: [M]+ m/z ) 1351.41. Found: TOFMS-ES: [M + Na]+
)
1374.61, [M + Na]2+ ) 698.28. MALDI-TOF: [M + Ag]+ ) 1447.
Anal. Calcd for C65H90O30: C, 57.77; H, 6.71. Found: C, 57.52; H,
6.86.
[G-3]-(O2Bn)12 (7). Generation growth was carried out using [G-2]-
(OH)12, 6, (426 mg, 315 µmol), and 154 mg (1.2 mmol) of DMAP in
3 mL of dry pyridine and 6 mL of CH2Cl2, followed by addition of
2.15 g (5.0 mmol) of anhydride 2, and stirring at room temperature for
5 h. Following workup as above, 7 was obtained as a white glass: 1100
mg, (92%). IR (cm-1, thin film from CHCl3): 3048, 1742 (s). 1H NMR
(300 MHz, CDCl3): δ 0.89 (s, 36), 1.12 (s, 9), 1.22 (s, 18), 2.04 (s, 3),
3.55 (d, 24, J ) 11.7), 4.15 (dd, 12, J ) 18.2, 11.2), 4.37 (s, 24), 4.54
(d, 24, J ) 11.4), 5.38 (s, 12), 6.90 (d, 6, J ) 9), 7.03 (d, 6, J ) 9),
7.27 (m, 36), 7.39 (m, 24). 13C NMR (500 MHz, CDCl3): δ 14.09,
17.28, 17.61, 17.69, 22.62, 25.24, 31.55, 34.63, 42.53, 46.79, 46.89,
65.13, 65.61, 73.39, 73.46, 101.61, 120.73, 126.13, 128.08, 128.81,
129.68, 137.79, 146.23, 148.49, 170.80, 171.89, 173.17. Calcd.: [M]+
m/z ) 3802.11. Found: MALDI-TOF: [M + Ag]+ ) 3901. Anal.
Calcd for C209H234O66: C, 66.02; H, 6.20. Found: C, 66.02; H, 6.39.
[G-3]-(OH)24 (8). [G-3]-(O2Bn)12 (7) (942 mg, 248 µmol) in 20 mL
of CH2Cl2 diluted with 20 mL of methanol and 50 mg Pd/C (10%)
were used for the deprotection to afford 8 as a white glass: 637 mg,
(94%). IR (cm-1, thin film from THF): 3424 (br), 1732 (s). 1H NMR
(500 MHz, DMSO-d6): δ 0.99 (s, 36), 1.19 (s, 18), 1.37 (s, 9), 2.15 (s,
3), 3.42 (m, 24), 4.14 (m, 24), 4.35 (dd, 12, J ) 26.5, 11), 4.65 (t, 24,
J ) 5.5), 7.05 (d, 6, J ) 9), 7.12 (d, 6, J ) 9). 13C NMR (500 MHz,
DMSO-d6): δ 16.75, 17.03, 17.22, 46.42, 46.60, 50.33, 63.73, 64.60,
65.89, 121.05, 129.49, 146.24, 148.35, 170.98, 171.95, 174.13.
Preparation of the First Generation Benzylidene-Protected
Dendrimer [G-1]-(O2Bn)3 and General Esterification Procedure by
Anhydride Coupling (3). 1,1,1-Tris(hydroxyphenyl)ethane 100 mg
(326 µmol) and 20 mg (160 µmol) of 4-(dimethylamino)pyridine
(DMAP) were dissolved in 2 mL of dry pyridine and then diluted with
6 mL of CH2Cl2. Solid anhydride 2 (556 mg, 1.3 mmol) was added,
and the reaction mixture was stirred at room temperature for 5 h. After
completion, according to MALDI-TOF, the excess benzylidene-2,2-
bis(oxymethyl)propionic anhydride (2) was quenched by stirring the
reaction mixture with 2 mL of a 1:1 pyridine:water solution overnight.
The organic phase was diluted with 100 mL of CH2Cl2 and extracted
with 2 × 40 mL of NaHSO4 (1 M), 2 × 40 mL of Na2CO3 (10%) and
1 × 40 mL of brine. The organic phase was dried using MgSO4 and
evaporated to give 3 as a white glass: 292 mg, (97%). IR (cm-1, thin
1
film from CHCl3): 3036, 1755 (s). H NMR (300 MHz, CDCl3): δ
1.21 (s, 9), 2.17 (s, 3), 3.75 (d, 6, J ) 11.4), 4.78 (d, 6, J ) 11.4), 5.52
(s, 3), 7.04 (d, 6, J ) 8.7), 7.11 (d, 6, J ) 9.0), 7.35 (m, 9), 7.46 (m,
6). 13C NMR (500 MHz, CDCl3): δ 17.67, 30.84, 42.85, 51.58, 73.50,
101.99, 120.83, 126.20, 128.25, 129.04, 129.62, 137.73, 146.12, 149.03,
172.69. Calcd.: [M]+ m/z ) 919.03. Found: TOFMS-ES: [M + Na]+
) 941.56, MALDI-TOFMS [M + Ag]+ ) 1033. Anal. Calcd for
C56H54O12: C, 73.19; H, 5.92. Found: C, 72.91; H, 5.95.
Calcd.: [M]+ m/z ) 2744.81. Found: TOFMS-ES: [M + Na]+
)
Preparation of the First Generation Hydroxyl-Terminated Den-
drimer [G-1]-(OH)6 (4) and General Procedure for the Removal
of the Benzylidene Group. [G-1]-(O2Bn)3 (3) (268 mg, 292 µmol)
was dissolved in 20 mL of CH2Cl2 and diluted with 15 mL of methanol.
50 mg Pd/C (10%) was added to the solution. 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 carefully washed with methanol. The filtrate was evaporated to
give 4 as white crystals: 185 mg, (97%). IR (cm-1, thin film from
2767.30, [M + Na]2+ ) 1395.23. Anal. Calcd for C125H186O66: C,
54.70; H, 6.83. Found: C, 54.68; H, 7.02.
[G-4]-(O2Bn)24 (9). Compound 9 was prepared as above using [G-3]-
(OH)24 (8) (443 mg, 161 µmol), 157 mg (1.29 mmol) of DMAP, 3 mL
of dry pyridine, and diluting with 6 mL of CH2Cl2, followed by the
addition of 2.20 g (5.0 mmol) of anhydride 2. Following the reaction,
9 was purified by precipitation into 200 mL of hexane under vigorous
stirring. After decantation, the precipitate was redissolved in CH2Cl2
1
and evaporated to give 7 as a white glass: 1150 mg, (93%). IR (cm-1
,
THF): 3369 (br), 1744 (s). H NMR (300 MHz, DMSO-d6): δ 1.18
thin film from CHCl3): 3047, 1741 (s). 1H NMR (300 MHz, CDCl3):
δ 0.89 (s, 72), 1.01 (s, 18), 1.17 (s, 36), 1.25 (s, 9), 2.06 (s, 3), 3.52 (d,
48, J ) 10.8), 4.07 (m, 24), 4.32 (m, 60), 4.52 (d, 48, J ) 11.4), 5.35
(s, 24), 6.92 (d, 6, J ) 8.4), 7.07 (d, 6, J ) 8.7), 7.26 (m, 72), 7.36 (m,
48). 13C NMR (500 MHz, CDCl3): δ 17.24, 17.44, 17.63, 17.66, 42.51,
46.49, 46.82, 46.85, 65.01, 65.27, 65.60, 73.36, 73.41, 101.58, 120.77,
126.17, 128.09, 128.82, 137.86, 146.36, 148.55, 170.71, 171.44, 171.85,
173.17. Calcd.: [M]+ m/z ) 7646.22. Found: MALDI -TOF [M +
(s, 9), 2.14 (s, 3), 3.53 (dd, 6, J ) 10.5, 5.4), 3.65 (dd, 6, J ) 10.5,
5.4), 4.92 (t, 6, J ) 10.8), 7.04 (q, 12, J ) 18.9, 8.7). 13C NMR (500
MHz, DMSO-d6): δ 16.92, 30.42, 50.88, 51.27, 64.00, 121.32, 129.17,
145.77, 149.00, 173.63. Calcd.: [M]+ m/z ) 654.71. Found: TOFMS-
ES: [M + Na]+ ) 677.43. Anal. Calcd for C35H42O12: C, 64.21; H,
6.47. Found: C, 64.12; H, 6.39.
[G-2]-(O2Bn)6 (5). [G-1]-(OH)6 (4), 328 mg (500 µmol), and 122
mg (1 mmol) of DMAP were dissolved in 2 mL of dry pyridine and
diluted with 6 mL of CH2Cl2. Following addition of 1.71 g (4.0 mmol)
of anhydride 2, the reaction mixture was stirred at room temperature
for 5 h. Excess anhydride was quenched with 2 mL of 1:1 pyridine:
water overnight. The organic phase was diluted with 100 mL of CH2-
Cl2 and extracted with 2 × 40 mL of NaHSO4 (1 M), 2 × 40 mL of
Na2CO3 (10%) and 1 × 40 mL of brine. The organic phase was dried
with MgSO4 and evaporated to give 5 as a white glass: 850 mg, (90%).
IR(cm-1, thin film from CHCl3): 3050, 1741 (s). 1H NMR (300 MHz,
Ag]+ ) 7742. Anal. Calcd for C413H474O138
: C, 64.88; H, 6.25.
Found: C, 65.05; H, 6.40.
[G-4]-(OH)48 (10). Debenzylation of [G-4]-(O2Bn)12 (9) (760 mg,
99 µmol) was carried out as above to give 10 as a white glass: 522
1
mg, (95%). IR (cm-1, thin film from THF): 3439 (br), 1736 (s). H
NMR (500 MHz, DMSO-d6): δ 0.97 (s, 72), 1.12 (s, 36), 1.18 (s, 18),
1.35 (s, 9), 2.14 (s, 3), 3.44 (m, 48), 4.08 (m, 48), 4.22 (m, 24), 4.36
(dd, 12, J ) 24.5, 10.0), 4.63 (t, 48, J ) 5.5), 7.05 (d, 6, J ) 8.0), 7.12

Aliphatic Ester Dendrimer Synthesis
J. Am. Chem. Soc., Vol. 123, No. 25, 2001 5915
(d, 6, J ) 7.5). 13C NMR (500 MHz, DMSO-d6): δ 16.73, 16.97, 17.18,
46.27, 46.56, 50.26, 63.69, 64.37, 65.28, 65.56, 121.02, 129.48, 146.25,
148.29, 170.80, 171.49, 171.88, 174.08. Calcd.: [M]+ m/z ) 5531.61.
Found: TOFMS-ES: [M + Na]+ ) 5553.58, [M + Na]2+ ) 2788.54,
[M + Na]3+ ) 1866.94. Anal. Calcd for C245H378O138: C, 53.20; H,
6.89. Found: C, 53.06; H, 7.06.
63.53, 67.11, 68.59, 70.35, 71.72, 84.02, 175.44. Calcd.: [M]+ m/z )
5,617. Found: MALDI-TOFMS: [M]+ ) 5610. PDI ) 1.03. Anal.
for 15: Found: C, 53.86; H, 9.08.
PEG-mono[G-2]-(O2Bn)2 (16). This was prepared as above using
15 (8.00, 1.5 mmol, 1.0 equiv), 18 mL of CH2Cl2, 2 (5.32 g, 12.5 mmol,
8.0 equiv), and DMAP (0.30 g, 2.5 mmol, 1.6 equiv) 15 h at room
temperature, followed by quenching with 5 mL of MeOH with 7 h of
stirring. Precipitation of the reaction mixture into 1,L of diethyl ether
afforded 7.82 g of product as a white powder (91%). IR (cm-1, thin
film from CHCl3): 2888, 1737, 1096. 1H NMR (300 MHz, CDCl3): δ
0.95 (s, 6), 1.26 (s, 3), 3.36 (s, 3), 3.63 (bs, ∼600), 3.79 (s, 4), 3.87 (t,
2, J ) 4.8), 4.12 (t, 2, J ) 4.8), 4.39 (s, 4), 4.58 (d, 4, J ) 11.4), 5.41
(s, 2), 7.32 (m, 6), 7.39 (m, 4). 13C NMR (500 MHz, CDCl3): δ. 17.68,
42.51, 46.70, 58.97, 64.15, 65.43, 68.62, 70.50, 71.86, 73.38, 101.63,
126.10, 128.04, 128.78, 137.74, 172.54, 173.16. Calcd.: [M]+ m/z )
6025. Found: MALDI-TOFMS: [M]+ ) 6020. PDI ) 1.03. Anal. for
16: Found: C, 55.10; H, 8.90.
PEG-mono[G-2]-(OH)4 (17). Polymer 16 (3.08 g, 0.56 mmol) was
deprotected as described above using 15 mL of 1:2 CH2Cl2:MeOH and
0.3 g of Pd/C catalyst for 10 h at room temperature under H2
atmosphere. After filtration and precipitation in 500 mL of diethyl ether,
2.76 g of 17 was obtained as a white powder (93%). IR (cm-1, thin
film from CHCl3): 3464, 2904, 1735, 1154. 1H NMR (400 MHz,
CDCl3): δ 1.07 (s, 6), 1.31 (s, 3), 3.37 (s, 3), 3.46 (m, 4), 3.64 (bs,
∼600), 3.81 (t, 8, J ) 5.2), 4.31 (m, 4), 4.40 (d, 2, J ) 10.8). 13C
NMR (500 MHz, CDCl3): δ. 17.08, 17.96, 46.40, 49.70, 58.95, 63.64,
64.33, 64.84, 67.39, 68.79, 70.47, 71.84, 84.15, 172.97, 174.97.
Calcd.: [M]+ m/z ) 5849. Found: MALDI-TOFMS: [M]+ ) 5848.
PDI ) 1.03. Anal. for 17: Found: C, 55.51; H, 9.07.
[G-5]-(O2Bn)48 (11). Generation growth for [G-4]-(OH)48 (10) (391
mg, 71 µmol) was carried out as above to afford 12 as a white glass
(after purification by precipitation): 972 mg, (90%). IR (cm-1, thin
1
film from CHCl3): 3050, 1738 (s). H NMR (500 MHz, CDCl3): δ
0.83 (s, 144), 1.00 (s, 36), 1.15 (s, 90), 1.34 (s, 9), 2.01 (s, 3), 3.49 (d,
96, J ) 10.5), 4.06 (m, 60), 4.31 (m, 120), 4.49 (d, 96, J ) 10.5), 5.32
(s, 48), 6.95 (d, 6, J ) 7), 7.06 (d, 6, J ) 7), 7.24 (m, 144), 7.36 (m,
96). 13C NMR (500 MHz, CDCl3): δ 17.25, 17.47, 17.60, 17.65, 42.47,
46.41, 46.48, 46.76, 47.00, 51.72, 64.93, 73.29, 73.34, 101.52, 120.81,
126.18, 128.07, 128.80, 137.93, 146.37, 148.65, 170.65, 171.41, 171.83,
173.15. Calcd.: [M]+ m/z ) 15 334.29. Found: MALDI-TOFMS: [M
+ Ag]+ ) 15 518. Anal. Calcd for C821H954O282: C, 64.31; H, 6.27.
Found: C, 63.12; H, 6.24.
[G-5]-(OH)96 (12). Deprotection of [G-5]-(O2Bn)48 (11) (300 mg,
19 µmol) as above afforded 12 as a white glass: 200 mg, (92%). IR
(cm-1, thin film from THF): 3419 (br), 1734 (s). 1H NMR (300 MHz,
DMSO-d6): δ 0.97 (s, 144), 1.13 (s, 108), 1.21 (s, 18), 1.35 (s, 9),
2.11 (s, 3), 3.40 (m, 192), 4.05 (m, 180), 4.56 (m, 96), 7.04 (d, 6, J )
7), 7.10 (d, 6, J ) 7). 13C NMR (500 MHz, DMSO-d6): δ 16.80, 17.05,
17.29, 46.23, 46.28, 50.29, 63.74, 64.00, 64.35, 65.04, 121.13, 129.52,
146.34, 148.39, 170.79, 171.50, 171.95, 174.15. Calcd.: [M]+ m/z )
11 105.07. Found: TOFMS-ES: [M + Na]2+ ) 5571.71, [M + Na]3+
) 3724.09, [M + Na]+4 ) 2799.73. Anal. Calcd for C485H762O282: C,
52.45; H, 6.92. Found: C, 51.42; H, 6.94.
PEG-mono[G-3]-(O2Bn)4 (18). This was prepared as above with
17 (5.58 g, 1.0 mmol, 1 equiv), 30 mL of CH2Cl2, anhydride 2 (8.6 g,
20.20 mmol, 20 equiv), and DMAP (0.25 g, 2 mmol, 2 equiv) stirred
for 18 h at room temperature. Following quenching with 5 mL of MeOH
for 8 h, the product was precipitated into 1 L of diethyl ether, affording
5.68 g of product as a white powder (91%). IR (cm-1, thin film from
[G-6]-(O2Bn)96 (13). Reaction of [G-5]-(OH)96 (12) (402 mg, 36
µmol) and 132 mg (1.1 mmol) DMAP with 1.85 g (4.3 mmol) of
anhydride 2, followed by quenching the excess anhydride, extracting,
and precipitating, afforded 13 as a white glass: 800 mg, (92%). IR
1
(cm-1, thin film from CHCl3): 3051, 1741 (s). H NMR (500 MHz,
1
CDCl3): δ 0.79 (s, 288), 0.99 (s, 72), 1.12 (s, 144), 1.23 (s, 18), 1.36
(s, 9), 1.92 (s, 3), 3.42 (d, 192, J ) 10.5), 4.05 (m, 132), 4.28 (m,
240), 4.44 (d, 192, J ) 10.5), 5.28 (s, 96), 6.93 (d, 6, J ) 7), 7.00 (d,
6, J ) 7), 7.23 (m, 288), 7.34 (m, 192). 13C NMR (500 MHz, CDCl3):
δ 17.25, 17.54, 17.64, 42.41, 46.34, 46.69, 64.81, 73.22, 101.41, 126.20,
128.04, 128.76, 138.00, 171.43, 171.81, 173.12. Calcd.: [M]+ m/z )
CHCl3): 2886, 1739, 1106. H NMR (400 MHz, CDCl3): δ 0.92 (s,
12), 1.04 (s, 3), 1.20 (s, 6), 3.38 (s, 3), 3.46 (m, 4), 3.64 (bs, ∼600),
3.81 (t, 3, J ) 4.8), 4.06 (q, 4, J ) 5.2), 4.17 (t, 2, J ) 4.8), 4.34 (m,
8), 4.56 (d, 8, J ) 11.6), 5.40 (s, 4), 7.30 (m, 12), 7.38 (m, 8). 13C
NMR (400 MHz, CDCl3): δ 17.18, 17.57, 17.61, 42.30, 46.34, 46.80,
58.94, 64.15, 65.06, 65.75, 70.49, 71.85, 73.35, 73.43, 101.95, 126.08,
128.02, 128.75, 137.75, 171.79, 172.01, 173.11. Calcd.: [M]+ m/z )
6665. Found: MALDI-TOFMS: [M]+ ) 6678. PDI ) 1.03. Anal. for
18: Found: C, 56.00; H, 8.44.
30 710.56. Found: MALDI-TOFMS: [M
+ ) 30 783.
Ag]+
Anal. Calcd for C1637H1914O570: C, 64.02; H, 6.28. Found: C, 63.86;
H, 6.13.
Preparation of the First Generation Benzylidene-Protected PEG-
mono[G-1]-(O2Bn) (14). The PEG monomethyl ether (Mn ) 5500,
PDI ) 1.03; 10.00 g, 2.0 mmol, 1 equiv) was dissolved in 30 mL of
CH2Cl2, anhydride 2 (1.71 g, 4.0 mmol, 2.0 equiv), and DMAP (0.10
g, 0.8 mmol, 0.4 equiv) was added. After stirring the reaction mixture
for 6 h at room temperature, 5 mL of MeOH was added to quench the
excess anhydride. After stirring for 5 h, the product was precipitated
into 1 L of diethyl ether. The precipitate was filtered through a glass
PEG-mono[G-3]-(OH)8 (19). Deprotection of 18 (2.14 g, 0.35
mmol) in 10 mL of 1:2 CH2Cl2:MeOH with Pd/C (10%, 0.2 g) for 15
h at room temperature under a H2 atmosphere followed by filtration
and precipitation in 500 mL of diethyl ether afforded 1.84 g of 19 as
a white powder (91%). IR (cm-1, thin film from CHCl3): 3455, 2885,
1
1737, 1106. H NMR (300 MHz, DMSO-d6): δ 1.01 (s, 12), 1.16 (s,
6), 1.19 (s, 3), 3.24 (s, 3), 3.51 (bs, ∼600), 3.66 (s, 4), 3.74 (t, 3, J )
4.8), 4.16 (m, 16), 4.63 (t, 8, J ) 5.4). 13C NMR (400 MHz, DMSO-
d6): δ 16.68, 16.97, 17.08, 46.09, 46.30, 50.24, 58.02, 63.65, 64.06,
64.47, 68.00, 69.57, 69.77, 71.37, 171.80, 171.98, 174.03. Calcd.: [M]+
m/z ) 6313. Found: MALDI-TOFMS: [M]+ ) 6302. PDI ) 1.03.
Anal. for 19: Found: C, 55.79; H, 8.75.
filter to afford 9.89 g of product as a white powder (95%). IR (cm-1
,
thin film from CHCl3): 2888, 1737, 1125. 1H NMR (300 MHz,
CDCl3): δ 1.05 (s, 3), 3.38 (s, 3), 3.42 (m, 3), 3.61 (bs, ∼600), 3.87
(t, 4, J ) 4.8), 4.36 (t, 2, J ) 4.8), 4.66 (d, 2, J ) 11.4), 5.44 (s, 1),
7.32 (m, 3), 7.42 (m, 2). 13C NMR (500 MHz, CDCl3): δ. 17.85, 42.38,
58.87, 63.67, 64.15, 69.00, 70.50, 71.87, 73.45, 101.69, 126.14, 128.12,
128.89, 137.81, 173.87. Calcd.: [M]+ m/z ) 5705. Found: MALDI-
TOFMS: [M]+ ) 5694. PDI ) 1.03. Anal. for 14: Found: C, 53.41;
H, 8.76.
PEG-mono[G-4]-(O2Bn)8 (20). This was prepared as above using
19 (2.63 g, 0.45 mmol, 1 equiv) in 25 mL of CH2Cl2, anhydride 2
(6.14 g, 14.40 mmol, 32 equiv) and DMAP (0.35 g, 2.9 mmol, 6.4
equiv) with stirring for 18 h at room temperature. After quenching with
5 mL of MeOH (7 h), the product was precipitated into 1 L of diethyl
ether, affording 2.97 g of 20 as a white powder (89%). IR (cm-1, thin
film from CHCl3): 2873, 1741, 1117. 1H NMR (300 MHz, CDCl3): δ
0.90 (s, 24), 1.01 (s, 6), 1.14 (s, 3), 1.19 (s, 12), 3.38 (s, 3), 3.62 (bs,
∼600), 3.88 (t, 2, J ) 4.8), 4.05 (s, 6), 4.15 (m, 6), 4.33 (m, 16), 4.55
(d, 16, J ) 11.7), 5.38 (s, 8), 7.29 (m, 24), 7.38 (m, 16). 13C NMR
(400 MHz, CDCl3): δ 17.10, 17.24, 17.58, 24.45, 46.42, 46.76, 58.92,
64.17, 64.97, 65.34, 66.04, 70.48, 71.84, 73.32, 73.38, 101.55, 126.08,
128.00, 128.73, 137.78, 171.30, 171.76, 173.07. Calcd.: [M]+ m/z )
7945. Found: MALDI-TOFMS: [M]+ ) 7950. PDI ) 1.03. Anal. for
20: Found: C, 56.94; H, 8.19.
PEG-mono[G-1]-(OH)2 (15). Polymer 14 (3.79 g, 0.73 mmol) was
dissolved in 25 mL of a 1:2 mixture of CH2Cl2 and MeOH, and the
catalyst (Pd/C 10%, 0.04 g) was added to the reaction mixture, followed
by evacuation of the system. The reaction mixture was stirred vigorously
for 6 h at room temperature under H2 atmosphere. After removal of
the catalyst by filtration, the product was precipitated in 500 mL of
diethyl ether, affording 3.57 g of a white powder (95%). IR (cm-1
,
thin film from CHCl3): 3476, 2893, 1726, 1129. 1H NMR (300 MHz,
CDCl3): δ 1.10 (s, 3), 3.37 (s, 3), 3.63 (bs, ∼600), 4.33 (t, 2, J ) 4.8).
13C NMR (500 MHz, CDCl3): δ 16.97, 49.49, 56.68, 58.83, 63.16,

5916 J. Am. Chem. Soc., Vol. 123, No. 25, 2001
Ihre et al.
PEG-mono[G-4]-(OH)16 (21). Compound 20 (1.21 g, 0.16 mmol)
in 12 mL of 1:2 CH2Cl2/MeOH was deprotected as described above to
0.90 g of 21 as a white powder (83%). IR (cm-1, thin film from
CHCl3): 3447, 2886, 1736, 1127. 1H NMR (300 MHz, DMSO-d6): δ
1.00 (s, 24), 1.16 (s, 12), 1.18 (s, 6), 1.21 (s, 3), 3.24 (s, 3), 3.51 (bs,
∼600), 3.72 (t, 3, J ) 4.8), 4.15 (m, 30), 4.63 (t, 16, J ) 5.4). 13C
NMR (400 MHz, DMSO-d6): δ 16.68, 16.83, 17.10, 46.19, 46.24,
50.21, 58.02, 63.64, 64.36, 69.77, 71.26, 171.35, 171.80, 174.01.
Calcd.: [M]+ m/z ) 7241. Found: MALDI-TOFMS: [M]+ ) 7240.
PDI ) 1.03. Anal. for 21: Found: C, 54.34; H, 8.46.
Preparation of the First Generation Benzylidene-Protected
Telechelic PEG-bis[G-1]-(O2Bn) (22). The telechelic PEG diol
(Mn ) 10 604 Da, PDI ) 1.03; 10.00 g, 0.91 mmol, 1 equiv) dissolved
in 25 mL of CH2Cl2 was treated with anhydride 2 (2.40 g, 5.5 mmol,
6 equiv) and DMAP (0.67 g, 0.55 mmol, 0.6 equiv). After stirring the
reaction mixture for 6 h at room temperature, 5 mL of MeOH was
added to quench the excess of anhydride. The mixture was stirred for
5 h, and the product was precipitated directly from the reaction mixture
into 1 L of diethyl ether to afford 9.86 g of product as a white powder
(95%). IR (cm-1, thin film from CHCl3): 2891, 1737, 1146. 1H NMR
(300 MHz, CDCl3): δ 1.04 (s, 6), 3.40 (t, 6, J ) 5.0), 3.63 (bs, ∼1100),
3.87 (t, 6, J ) 5.0), 4.35 (t, 4, J ) 5.0), 4.66 (d, 4, J ) 11.4), 5.44 (s,
2), 7.32 (m, 6), 7.41 (m, 4). 13C NMR (500 MHz, CDCl3): δ 17.80,
42.34, 56.78, 63.63, 64.11, 68.96, 70.46, 73.40, 101.65, 126.10, 128.07,
128.85, 137.77, 173.82. Calcd.: [M]+ m/z ) 11 014. Found: MALDI-
TOFMS: [M]+ ) 11 032. PDI ) 1.03. Anal. for 22: Found: C, 54.65;
H, 8.82.
Removal of the Protecting Groups: Preparation of Telechelic
PEG-bis[G-1]-(OH)2 (23). The protecting groups at both ends of 22
(7.95 g, 0.7 mmol) dissolved in 40 mL of 1:2 CH2Cl2:MeOH were
removed as described above (Pd/C 10%, 0.2 g, 8 h at room temperature
under H2). After precipitation in 1 L of diethyl ether, 7.36 g of 23
were obtained as a white powder (94%). IR (cm-1, thin film from
CHCl3): 3479, 2889, 1728, 1148. 1H NMR (400 MHz, CDCl3): δ 1.12
(s, 6), 3.64 (bs, ∼1100), 4.33 (t, 4, J ) 5.0). 13C NMR (500 MHz,
CDCl3): δ 17.02, 49.52, 56.60, 63.34, 63.44, 66.64, 68.65, 70.17, 83.94,
175.45. Calcd.: [M]+ m/z ) 10 838. Found: MALDI-TOFMS: [M]+
) 10 838. PDI ) 1.03. Anal. for 23: Found: C, 53.16; H, 8.27.
Telechelic PEG-bis[G-2]-(O2Bn)2 (24). Generation growth was
carried out as above using 23 (12.19 g, 1.1 mmol, 1 equiv) in 40 mL
of CH2Cl2 anhydride 2 (7.44 g, 17.4 mmol, 16 equiv) and DMAP (0.43
g, 3.5 mmol, 3.2 equiv). Yield: 11.74 g of white powder (89%). IR
(cm-1, thin film from CHCl3): 2887, 1738, 1097. 1H NMR (400 MHz,
CDCl3): δ 0.95 (s, 12), 1.26 (s, 6), 3.64 (bs, ∼1100), 3.81 (t, 4, J )
4.8), 4.13 (t, 4, J ) 4.8), 4.39 (s, 8), 4.59 (d, 8, J ) 11.6), 5.42 (s, 4),
7.40 (m, 12), 7.47 (m, 8). 13C NMR (500 MHz, CDCl3): δ 17.55, 17.58,
42.41, 46.60, 58.86, 63.57, 64.05, 65.32, 68.52, 70.40, 71.76, 73.28,
73.37, 83.96, 101.52, 126.01, 127.94, 128.68, 137.65, 172.44, 173.06.
Calcd.: [M]+ m/z ) 11 654. Found: MALDI-TOFMS: [M]+ ) 11 631.
PDI ) 1.03. Anal. for 24: Found: C, 54.70; H, 8.46.
171.90, 172.98. Calcd.: [M]+ m/z ) 12 934. Found: MALDI-
TOFMS: [M]+ ) 12 946. PDI ) 1.03. Anal. for 26: Found: C, 56.06;
H, 8.33.
Telechelic PEG-bis[G-3]-(OH)8 (27). Deprotection of 26 (8.10 g,
0.61 mmol) in 45 mL of 1:2 CH2Cl2:MeOH, for 18 h at room
temperature under H2 atmosphere afforded 6.82 g of a white powder
(89%). IR (cm-1, thin film from CHCl3): 3461, 2886, 1735, 1104. 1H
NMR (500 MHz, CDCl3): δ 1.07 (s, 24), 1.29 (s, 6), 1.30 (s, 12), 3.28
(t, 5, J ) 5.8), 3.35 (t, 5, J ) 5.8), 3.50 (t, 6, J ) 5.8), 3.64 (bs, ∼1100),
3.78 (m, 25), 4.30 (m, 20), 4.36 (dd, 10, J ) 11.0, 5.0). 13C NMR (500
MHz, DMSO-d6): δ 16.71, 16.99, 17.10, 46.11, 46.32, 50.26, 62.96,
63.65, 64.09, 64.50, 65.70, 68.02, 69.78, 76.61, 83.46, 171.83, 172.01,
174.06. Calcd.: [M]+ m/z ) 12 230. Found: MALDI-TOFMS: [M]+
) 12 229. PDI ) 1.03. Anal. for 27: Found: C, 53.38; H, 8.19.
Telechelic PEG-bis[G-4]-(O2Bn)8 (28). Generation growth was
carried out as above using 27 (4.61 g, 0.37 mmol, 1 equiv) in 50 mL
of CH2Cl2, anhydride 2 (9.96 g, 23.3 mmol, 64 equiv), and DMAP
(0.57 g, 4.6 mmol, 13 equiv), for 18 h at room temperature. After
precipitation in diethyl ether, 5.01 g of product was obtained as a white
powder (86%). IR (cm-1, thin film from CHCl3): 2885, 1741, 1105.
1H NMR (300 MHz, CDCl3): δ 0.90 (s, 48), 1.01 (s, 12), 1.14 (s, 6),
1.19 (s, 24), 3.40 (t, 10, J ) 5.8), 3.64 (bs, ∼1100), 3.80 (s, 5), 3.87
(t, 3, J ) 5.8), 4.04 (s, 12), 4.13 (m, 12), 4.33 (dd, 32, J ) 11.7, 5.0),
4.54 (d, 32, 11.4), 5.38 (s, 16), 7.29 (m, 48), 7.38 (m, 32). 13C NMR
(400 MHz, CDCl3): δ 17.15, 17.63, 42.50, 46.42, 46.45, 46.79, 63.68,
64.22, 64.99, 65.35, 66.07, 70.51, 73.37, 73.43, 101.60, 126.13, 128.06,
128.79, 137.81, 171.34, 171.81, 173.12. Calcd.: [M]+ m/z ) 15 494.
Found: MALDI-TOFMS: [M]+ ) 15 510. PDI ) 1.03. Anal. for 28:
Found: C, 57.08; H, 7.91.
Telechelic PEG-bis[G-4]-(OH)16 (29). Deprotection of 28 (4.50 g,
0.28 mmol) as above afforded 3.26 g of a white powder (80%). IR
(cm-1, thin film from CHCl3): 3454, 2883, 1738, 1107. 1H NMR (300
MHz, DMSO-d6): δ 1.00 (s, 48), 1.16 (s, 24), 1.17 (s, 12), 1.21 (s, 6),
3.27 (t, 8, J ) 5.8), 3.64 (bs, ∼1100), 3.66 (s, 16), 3.74 (t, 12, J )
5.0), 4.15 (m, 68), 4.63 (t, 32, J ) 5.4). 13C NMR (500 MHz, DMSO-
d6): δ 16.71, 16.86, 17.14, 46.21, 46.27, 50.24, 62.98, 63.64, 64.14,
64.37, 65.33, 66.11, 68.01, 69.80, 76.62, 171.39, 171.83, 174.05.
Calcd.: [M]+ m/z ) 14 086. Found: MALDI-TOFMS: [M]+ ) 14 090.
PDI ) 1.03. Anal. for 29: Found: C, 52.79; H, 7.70.
Preparation of the First Generation Benzylidene-Protected Four-
Arm Star PEG-tetra[G-1]-(O2Bn) (30). The 4-arm PEG star (Mn )
20 330 Da, PDI ) 1.10; 10.00 g, 0.50 mmol, 1 equiv) dissolved in 30
mL of CH2Cl2 was treated with anhydride 2 (1.71 g, 4.0 mmol, 8 equiv)
and DMAP (0.10 g, 0.8 mmol, 1.6 equiv), and the mixture was stirred
for 15 h at room temperature. After quenching the excess anhydride
with 5 mL of MeOH and stirring for 7 h, the product was precipitated
directly from the reaction mixture into 1 L of diethyl ether. The
precipitate was filtered through a glass filter, affording 10.02 g of
product as a white powder (96%). IR (cm-1, thin film from CHCl3):
1
2884, 1736, 1106. H NMR (300 MHz, CDCl3): δ 1.03 (s, 12), 3.39
(m, 20), 3.62 (bs,), 3.77 (s, 22), 3.86 (t, 14, J ) 4.5), 4.34 (t, 8, J )
4.8), 4.65 (d, 8, J ) 10.5), 5.43 (s, 4), 7.31 (m, 12), 7.40 (m, 8). 13C
NMR (500 MHz, CDCl3): δ 17.85, 42.39, 64.16, 69.01, 70.50, 73.45,
101.70, 126.15, 128.13, 128.90, 137.81, 173.88. Calcd.: [M]+ m/z )
21 150. Found: MALDI-TOFMS: [M]+ ) 21 139. PDI ) 1.10. Anal.
for 30: Found: C, 54.42; H, 8.71.
Telechelic PEG-bis[G-2]-(OH)4 (25). Deprotection of 24 (11.45 g,
0.95 mmol) in 70 mL of (1:2) CH2Cl2:MeOH was carried out as above
for 16 h at room temperature under H2 atmosphere. Yield: 10.27, white
powder (92%). IR (cm-1, thin film from CHCl3): 3466, 2886, 1730,
1
1147. H NMR (300 MHz, CDCl3): δ 1.07 (s, 12), 1.31 (s, 6), 3.26
(m, 8), 3.40 (t, 6, J ) 4.8), 3.64 (bs, ∼1100), 4.32 (m, 8), 4.40 (d, 4,
J ) 11.1). 13C NMR (500 MHz, CDCl3): δ 17.04, 17.92, 46.35, 49.67,
56.75, 63.60, 64.28, 64.79, 67.27, 68.74, 70.42, 84.10, 172.93, 174.89.
Calcd.: [M]+ m/z ) 11 302. Found: MALDI-TOFMS: [M]+ ) 11 292.
PDI ) 1.03. Anal. for 25: Found: C, 53.31; H, 8.39.
Telechelic PEG-bis[G-3]-(O2Bn)4 (26). Generation growth was
carried out as described above with 25 (8.02 g, 0.7 mmol, 1 equiv) in
60 mL of CH2Cl2, anhydride 2 (9.36 g, 22 mmol, 32 equiv) and DMAP
(0.54 g, 4.4 mmol, 6.4 equiv) for 15 h at room temperature. Yield 8.44
g, white powder (92%). IR (cm-1, thin film from CHCl3): 2894, 1741,
1128. 1H NMR (400 MHz, CDCl3): δ 0.93 (s, 24), 1.04 (s, 6), 1.20 (s,
12), 3.46 (t, 6, J ) 4.8), 3.64 (bs, ∼1100), 3.81 (t, 3, J ) 4.8), 4.08 (q,
6, J ) 5.8), 4.28 (t, 3, J ) 4.8), 4.34 (m, 16), 4.56 (d, 16, J ) 11.6),
5.40 (s, 8), 7.30 (m, 24), 7.39 (m, 16). 13C NMR (400 MHz, CDCl3):
δ 17.07, 17.46, 17.50, 42.36, 46.23, 46.68, 64.04, 64.94, 65.61, 68.48,
70.37, 73.23, 73.31, 101.46, 125.97, 127.90, 128.62, 137.66, 171.67,
Deprotection of 30, Preparation of Four-Arm PEG-tetra[G-1]-
(OH)2 (31). Removal of the benzylidene groups of 30 (10.40 g, 0.5
mmol) dissolved in 60 mL of 1:2 CH2Cl2:MeOH was achieved using
Pd/C (10%, 0.25 g) for 18 h at room temperature under H2 atmosphere.
The catalyst was removed from the reaction mixture by filtration using
a glass filter. The product was precipitated in 1 L of diethyl ether,
affording 10.02 g of a white powder (98%). IR (cm-1, thin film from
CHCl3): 3477, 2885, 1733, 1104. 1H NMR (400 MHz, CDCl3): δ 1.11
(s, 12), 3.06 (t, 10, J ) 4.5), 3.41 (s, 10), 3.46 (t, 10, J ) 4.0), 3.64
(bs, ∼2100), 3.80 (m, 18), 4.34 (t, 8, J ) 4.8). 13C NMR (500 MHz,
CDCl3): δ 17.01, 45.20, 49.52, 63.23, 63.60, 67.21, 68.63, 70.24, 80.10,
175.50. Calcd.: [M]+ m/z ) 20 798. Found: MALDI-TOFMS: [M]+
) 20 812. PDI ) 1.11. Anal. for 31: Found: C, 54.28; H, 8.61.
Four-Arm PEG-tetra[G-2]-(O2Bn)2 (32). Generation growth of 31
(6.78 g, 0.33 mmol, 1 equiv) was carried out as above with anhydride

Aliphatic Ester Dendrimer Synthesis
J. Am. Chem. Soc., Vol. 123, No. 25, 2001 5917
2 (5.65 g, 13.2 mmol, 40 equiv) and DMAP (0.16 g, 1.3 mmol, 4 equiv)
for 16 h at room temperature. Yield: 7.01 g, white powder (96%). IR
(cm-1, thin film from CHCl3): 2887, 1739, 1130. 1H NMR (300 MHz,
CDCl3): δ 0.95 (s, 24), 1.26 (s, 12), 3.63 (bs, ∼2100), 3.79 (m, 20),
3.87 (m, 8), 4.13 (t, 6, J ) 4.8), 4.39 (s, 16), 4.58 (d, 16, J ) 11.7),
5.41 (s, 8), 7.30 (m, 24), 7.38 (m, 16). 13C NMR (500 MHz, CDCl3):
δ 17.50, 17.53, 42.36, 45.30, 46.55, 56.65, 63.55, 64.01, 65.27, 68.47,
70.35, 73.23, 73.31, 84.10, 101.47, 125.96, 127.89, 128.63, 137.61,
172.39, 173.01. Calcd.: [M]+ m/z ) 22 430. Found: MALDI-
TOFMS: [M]+ ) 22 397. PDI ) 1.11. Anal. for 32: Found: C, 55.17;
H, 8.48.
Four-Arm PEG-tetra[G-2]-(OH)4 (33). Deprotection of 32 (3.35
g, 0.15 mmol) in 16 mL of (1:2) CH2Cl2/MeOH afforded 3.09 g of a
white powder (95%). IR (cm-1, thin film from CHCl3): 3462, 2883,
1734, 1107. 1H NMR (300 MHz, CDCl3): δ 1.07 (s, 24), 1.31 (s, 12),
3.38 (m, 20), 3.64 (bs, ∼2100), 3.83 (s, 32), 3.87 (m, 16), 4.30 (m,
16), 4.40 (d, 8, J ) 11.1). 13C NMR (400 MHz, CDCl3): δ 17.10,
17.95, 46.43, 49.74, 64.34, 64.88, 67.39, 68.81, 70.56, 172.98, 174.98.
Calcd.: [M]+ m/z ) 21 726. Found: MALDI-TOFMS: [M]+ ) 21 728.
PDI ) 1.11. Anal. for 33: Found: C, 53.54; H, 8.67.
Four-Arm PEG-tetra[G-4]-(O2Bn)8 (36). Generation growth of 35
(1.94 g, 0.08 mmol, 1 equiv) dissolved in 25 mL of CH2Cl2 was carried
out as above using anhydride 2 (4.53 g, 10.6 mmol, 128 equiv) and
DMAP (0.13 g, 1.1 mmol, 12.8 equiv) with stirring for 18 h at room
temperature. After quenching and precipitation into 500 mL of diethyl
ether, 1.73 g of product was obtained as a white powder (70%). IR
(cm-1, thin film from CHCl3): 2883, 1741, 1126. 1H NMR (300 MHz,
CDCl3): δ 0.90 (s, 96), 1.01 (s, 24), 1.14 (s, 12), 1.19 (s, 48), 3.64
(bs, ∼2100), 3.87 (t, 8, J ) 5.1), 4.04 (s, 28), 4.14 (m, 22), 4.34 (dd,
64, J ) 15.2, 3.3), 4.54 (d, 64, J ) 11.4), 5.38 (s, 32), 7.29 (m, 96),
7.38 (m, 64). 13C NMR (500 MHz, CDCl3): δ 17.13, 17.61, 42.48,
46.40, 46.43, 46.77, 64.97, 65.34, 66.06, 70.27, 70.50, 73.35, 73.41,
101.58, 126.11, 128.05, 128.78, 137.79, 171.33, 171.80, 173.11.
Calcd.: [M]+ m/z ) 30 110. Found: MALDI-TOFMS: [M]+ ) 30 094.
PDI ) 1.08. Anal. for 36: Found: C, 56.95; H, 8.02.
Four-Arm PEG-tetra[G-4]-(OH)16 (37). Deprotection of 36 (1.54
g, 0.05 mmol) as above followed by precipitation in 500 mL of diethyl
ether afforded 1.19 g of a white powder (85%). IR (cm-1, thin film
1
from CHCl3): 3456, 2883, 1737, 1108. H NMR (300 MHz, DMSO-
d6): δ 1.01 (s, 96), 1.16 (s, 48), 1.17 (s, 24), 1.21 (s, 12), 3.50 (bs,
Four-Arm PEG-tetra[G-3]-(O2Bn)4 (34). Generation growth of 33
(2.93 g, 0.14 mmol, 1 equiv) in 30 mL of CH2Cl2 was carried out as
above using anhydride 2 (4.67 g, 11 mmol, 80 equiv) and DMAP (0.13
g, 1.1 mmol, 8 equiv) to afford 3.10 g of product as a white powder
(92%). IR (cm-1, thin film from CHCl3): 2885, 1741, 1126. 1H NMR
(400 MHz, CDCl3): δ 0.92 (s, 48), 1.04 (s, 12), 1.20 (s, 24), 3.63 (bs,
∼2100), 4.07 (m, 8), 4.18 (s, 4), 4.34 (s, 32), 4.55 (d, 32, J ) 11.7),
5.40 (s, 16), 7.29 (m, 48), 7.38 (m, 32). 13C NMR (400 MHz, CDCl3):
δ 17.23, 17.62, 17.66, 42.52, 46.40, 46.85, 64.19, 65.11, 65.80, 70.53,
73.41, 73.48, 101.65, 126.14, 128.07, 128.79, 137.81, 171.85, 173.14.
Calcd.: [M]+ m/z ) 24 490. Found: MALDI-TOFMS: [M]+ ) 24 984.
PDI ) 1.11. Anal. for 34: Found: C, 55.53; H, 8.18.
∼2100), 3.74 (t, 12, J ) 5.1), 4.14 (m, 116), 4.63 (t, 64, J ) 5.4). 13
C
NMR (500 MHz, DMSO-d6): δ 17.07, 17.38, 17.49, 17.87, 46.51,
46.53, 46.65, 49.93, 64.74, 66.21, 70.49, 172.44, 174.94. Calcd.: [M]+
m/z ) 27 294. Found: MALDI-TOFMS: [M]+ ) 27 280. PDI ) 1.10.
Anal. for 37: Found: C, 54.19; H, 8.20.
Acknowledgment. Financial support of this work by the
ARO-MURI program and the National Science Foundation
(DMR #9816166) is gratefully acknowledged. Thanks are also
due to the Swedish Foundation for International Cooperation
in Research and Education for partial Fellowship support (H.I.).
We also thank Nippon Oils and Fats of America for graciously
supplying the PEG cores. Dr. Nikolay Vladimirov and Ms.
Barbara Mun˜oz are also thanked for assistance in MALDI-
TOFMS and SEC characterization and in the synthesis of some
hybrids. The Center for New Directions in Organic Synthesis
is supported by Bristol-Myers Squibb as sponsoring member.
Four-Arm PEG-tetra[G-3]-(OH)8 (35). Deprotection of 34 (2.87
g, 0.12 mmol) afforded 2.10 g of a white powder (78%). IR (cm-1
,
thin film from CHCl3): 3455, 2885, 1737, 1124. 1H NMR (400 MHz,
DMSO-d6): δ 1.01 (s, 48), 1.16 (s, 24), 1.19 (s, 12), 3.51 (bs, ∼2100),
4.14 (m, 54), 4.63 (t, 32, J ) 5.4)). 13C NMR (400 MHz, DMSO-d6):
δ 16.68, 16.95, 17.08, 46.09, 46.30, 50.24, 63.65, 64.47, 69.77, 171.81,
171.98, 174.03. Calcd.: [M]+ m/z ) 23 582. Found: MALDI-
TOFMS: [M]+ ) 23 582. PDI ) 1.16. Anal. for 35: Found: C, 53.59;
H, 8.44.
JA010524E