Rapid synthesis of dendrimers by an orthogonal coupling strategy

Full text of DOI:10.1021/ja960317s

5326
J. Am. Chem. Soc. 1996, 118, 5326-5327
Scheme 1a
Rapid Synthesis of Dendrimers by an Orthogonal
Coupling Strategy
Fanwen Zeng and Steven C. Zimmerman*
Department of Chemistry, UniVersity of Illinois
Urbana, Illinois 61801
ReceiVed January 30, 1996
Dendrimers are polymers that radiate out from a central core,
with the number of branch points on a given arm increasing
exponentially from the core to the periphery.1 Because of their
novel properties, dendrimers have found many uses, including
as unimolecular micelles,2 novel amphiphiles,3 complexation
agents,4 and MRI contrast agents.5 These and other applications
will benefit from more efficient methods of dendrimer prepara-
tion because the iterative synthetic approaches to even small
dendrons are multistep. In particular, both the divergent
approach developed by Tomalia6 and Newkome7 and the
convergent method of Fre´chet8 minimally require a deprotection
or activation step in addition to the coupling step that adds each
new generation. Several successful attempts to shorten these
synthetic sequences were reported;9-11 however, these ap-
proaches still require (de)protection or activation chemistry.
Several years ago, Baranay and Merrifield12 defined an
orthogonal system as “a set of completely independent classes
of protection groups, such that each class can be removed in
any order and in the presence of all other classes.” Orthogonal
protecting group strategies have found widespread use in peptide
chemistry, and recently Ogawa13 used two independent (or-
thogonal) glycosylation reactions to accelerate the synthesis of
oligosaccharides. We now describe a rapid synthesis of
dendrimers using an orthogonal coupling strategy wherein each
synthetic step adds a generation to the existing dendrimer.14
In the orthogonal approach the protection or activation steps
are eliminated by sequential use of two different building blocks
in two orthogonal coupling reactions. The current study uses
AB2 monomer units 1 and 215 which contain two pairs of
a Reaction conditions: (a) PPh3, diethyl azodicarboxylate (DEAD),
THF; (b) Pd(PPh3)2Cl2, CuI, or Pd2(dba)3, CuI, PPh3, Et3N, PhCH3.
complementary coupling functionality. These monomer units
were designed to couple by the Mitsunobu esterification
reaction16 or by the Sonogashira reaction of a terminal acetylene
with an aryl iodide.17 The latter reaction has been used
extensively by Moore in the preparation of phenylacetylene
dendrimers and other nanostructures.18 It was anticipated that
both pairs of functional groups and their resulting coupling
products would be inert to the conditions of the other coupling
reaction, orthogonality that would allow 1 and 2 to be employed
consecutively in either order.
(1) For very recent reviews, see: Voit, B. I. Acta Polym. 1995, 46, 87-
99. Ardoin, N.; Astruc, D. Bull. Soc. Chim. Fr. 1995, 132, 875-909. See
also refs 6, 7, and 18a.
(2) Newkome, G. R.; Moorefield, C. N.; Baker, G. R.; Saunders, M. J.;
Grossman, S. H. Angew. Chem. 1991, 103, 1207-1209. Hawker, C. J.;
Wooley, K. L.; Fre´chet, J. M. J. J. Chem. Soc., Perkin Trans. 1 1993, 1287-
1297. Kim, Y. H.; Webster, O. W. J. Am. Chem. Soc. 1990, 112, 4592-
4593. For metal-binding dendrimers, see: Nagasaki, T.; Kimura, O.; Ukon,
M.; Arimori, S.; Hamachi, I.; Shinkai, S. J. Chem. Soc., Perkin Trans. 1
1994, 75-81.
(3) Chapman, T. M.; Hillyer, G. L.; Mahan, E. J.; Shaffer, K. A. J. Am.
Chem. Soc. 1994, 116, 11195-11196. van Hest, J. C. M.; Delnoye, D. A.
P.; Baars, M. W. P. L.; van Genderen, M. H. P.; Meijer, E. W. Science
1995, 268, 1592-1595.
(4) Jansen, J. F. G. A.; Meijer, E. W.; de Brabander-van den Berg, E.
M. M. J. Am. Chem. Soc. 1995, 117, 4417-4418.
(14) To our knowledge, orthogonal dendrimer syntheses have been
attempted only twice: (a) Twyman, L. J.; Beezer, A. E.; Mitchell, J. C. J.
Chem. Soc., Perkin Trans. 1 1994, 407-411. (b) Spindler, R.; Fre´chet, J.
M. J. J. Chem. Soc., Perkin Trans. 1 1993, 913-918. Both syntheses were
carried to the third-generation stage. In ref 14a orthogonality was not
demonstrated, whereas in ref 14b it was achieved, but the third-generation
dendrimer could not be separated from byproducts.
(5) Wiener, E. C.; Brechbiel, M. W.; Brothers, H.; Magin, R. L.; Gansow,
O. A.; Tomalia, D. A.; Lauterbur, P. C. Magn. Reson. Med. 1994, 31, 1-8.
(6) Tomalia, D. A.; Durst, H. D. Top. Curr. Chem. 1993, 165, 193-
313. Tomalia, D. A. Aldrichimica Acta 1993, 26, 91-101. For early
examples, see: Denkewalter, R. G.; Kole, J. F.; Lukasavage, W. J. U.S.
Patent 4 410 688, 1979. Buhleier, E.; Wehner, W.; Vo¨gtle, F. Synthesis
1978, 155-158.
(15) (a) Monomer 1 was prepared by diazotization of commercially
available 5-aminoisophthalic acid followed by treatment with sodium iodide
(72% yield). Alcohol 2 was prepared from methyl 3,5-dibromobenzoate
by reduction, coupling to (trimethylsilyl)acetylene, and deprotection with
potassium carbonate (79% overall yield). (b) All compounds had spectral
data in full accord with the assigned structures. Each compound except
14-16 was submitted for combustion analysis and gave passing results.
The purity of 14-16 was estimated to be >97% from SEC and HPLC
traces which each showed a single sharp peak. (c) Of course, the three
steps do not include the several steps needed to make 8 and 9. The important
point is that the orthogonal strategy minimizes the number of steps in the
actual dendrimer synthesis, where purification is particularly difficult. The
13 to 14-16 conversion was carried out on a 200-600 mg scale; all other
reactions were carried out on >1 g scale.
(7) Moorefield, C. N.; Newkome, G. R.; Baker, G. R. Aldrichimica Acta
1992, 25, 31-38.
(8) (a) Hawker, C. J.; Fre´chet, J. M. J. J. Am. Chem. Soc. 1990, 112,
7638-7647. (b) See also: Miller, T. M.; Neenan, T. X.; Zayas. R.; Bair,
H. E. J. Am. Chem. Soc. 1992, 114, 1018-1025.
(9) Wooley K. L.; Hawker, C. J.; Fre´chet, J. M. J. J. Am. Chem. Soc.
1991, 113, 4252-4261. Xu, Z.; Kahr, M.; Walker, K. L.; Wilkins, C. L.;
Moore, J. S. J. Am. Chem. Soc. 1994, 116 , 4537-4550.
(10) Wooley K. L.; Hawker, C. J.; Fre´chet, J. M. J. Angew. Chem., Int.
Ed. Engl. 1994, 33, 82-85.
(16) Mitsunobu, O. Synthesis 1981, 1-28. Hughes, D. L. Org. React.
1992, 42, 335-656.
(17) Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett. 1975,
4467-4470. Cassar, L. J. Organomet. Chem. 1975, 93, 253-257. Dieck,
H. A.; Heck, R. F. J. Organomet. Chem. 1975, 93, 259-263.
(18) (a) Xu, Z.; Kyan, B.; Moore, J. S. In AdVances in Dendritic
Macromolecules; Newkome, G. R., Ed.; JAI: Greenwich,CT, 1994; Vol.
1, p 69. (b) Zhang, J. S.; Pesak, D. J.; Ludwick, J. L.; Moore, J. S. J. Am.
Chem. Soc. 1994, 116, 4227-4239.
(11) Kawaguchi, T.; Walker, K. L.; Wilkins, C. L.; Moore, J. S. J. Am.
Chem. Soc. 1995, 117, 2159-2165.
(12) Baranay, G.; Merrifield, R. B. J. Am. Chem. Soc. 1977, 99, 7363-
7365.
(13) Kanie, O.; Ito, Y.; Ogawa, T. J. Am. Chem. Soc. 1994, 116, 12073-
12074.
S0002-7863(96)00317-4 CCC: $12.00 © 1996 American Chemical Society

Communications to the Editor
J. Am. Chem. Soc., Vol. 118, No. 22, 1996 5327
Scheme 2a
Scheme 3a
a Reaction conditions: (a) MeOH, H2SO4 (96%); (b) LiAlH4, Et2O
(79%); (c) Dimethyl 5-hydroxyisophthalate (10), PPh3, DEAD (73%);
(d) KOH, H2O (93%); (e) PPh3, CBr4 (87%); (f) 3,5-Dihydroxybenzyl
alcohol (11), K2CO3 (82%).
The application of this orthogonal coupling strategy to the
synthesis of a fourth-generation dendron is outlined in Scheme
1. (4-tert-Butylphenoxy)ethanol (3) was coupled to 1 under
Mitsunobu conditions to give first-generation dendron 4 in 80%
yield. At the focal point of dendron 4 is an iodide group, which
coupled to 2 using the Sonogashira reaction to form second-
generation dendron 5 in 82% yield. The alcohol group at the
focal point of this dendron was set to react with diacid 1, again
under Mitsunobu conditions. In the event, coupling of 1 and 5
afforded third-generation dendron 6 in 80% yield. In a final
iteration, 6 coupled to 2 to produce fourth-generation dendron
7 in 78% yield. By alternate use of 1 and 2 in their respective
orthogonal reactions, the fourth-generation dendron 7 was
synthesized in four steps.
To further increase the efficiency of this strategy, the
orthogonal coupling method was merged with Fre´chet’s branched-
monomer approach.10 Two new “branched monomers” 8 and
9, already at the second-generation stage, were used for this
purpose. These compounds contain the same functionality as
do 1 and 2 but are expanded by an ether linkage and have four
peripheral reaction sites. Compound 8 was obtained in four
steps from 1 (Scheme 2). The desired monomer 9 was prepared
in two steps by conversion of 2 to the corresponding bromide
which was coupled to 11.
Scheme 3 illustrates the synthesis of a sixth-generation
dendron from 8 and 9 using the orthogonal coupling approach.
Tetraesterification of alcohol 3 with tetraacid 8 under Mitsunobu
conditions afforded second-generation iodide 12 in 84% yield.
Coupling of this iodide with tetraacetylene 9 under Sonogashira
conditions afforded fourth-generation dendron 13 in 66% yield.
Alcohol 13, an analog of 7, was used to synthesize higher
generation dendrimers. Thus, esterification of 13 with diacid
1, trimesic acid, and tetraacid 8 under Mitsunobu conditions
afforded the corresponding dendron 14 (G5I), dendrimer 15
((G4)3), and dendron 16 (G6I) in 80%, 46%, and 62% yield,
respectively. The yields of these coupling reactions are based
on relatively low conversions of 13 to 14 (46%), 15 (41%),
and 16 (22%), which likely reflects the congestion at the focal
point.19 Thus, from 8 and 9, the synthesis of sixth-generation
dendron 16 required only three steps and two chromatographic
separations.15c
All the dendrimers were characterized by standard spectro-
scopic methods15b and by size-exclusion chromatography (SEC)
with differential refractometer index (DRI) and dual-angle laser
light scattering (LLS) detectors. The molecular weights were
determined directly by LLS and from their retention times using
polystyrene standards. Although the latter method underesti-
mated the molecular weight of high-generation (>4) dendrimers
because of their compactness,8a results from the laser light
scattering technique were in good agreement with the theoretical
values.20 The dendrimers were also characterized by mass
a Same reaction conditions as in Scheme 1.
spectrometry using matrix-assisted laser desorption ionization
(MALDI). In the MALDI spectra, the major peaks often
appeared 23 or 39 mass units higher than the corresponding
molecular ions, presumably representing sodium or potassium
ion adducts.21
In comparison to the most efficient dendrimer syntheses
available, the orthogonal coupling approach halves the number
of steps needed by obviating (de)protection or activation steps.
Each synthetic step adds at least one generation to the dendrimer.
As a case in point, sixth-generation dendron 16, with molecular
formula C1292H1369IO242 and a molecular weight of 20 896 g
mol-1, was synthesized in just three steps from 8 and 9. There
is nothing special about the reactions and subunits in Schemes
1-3; they were chosen simply to demonstrate the orthogonal
coupling strategy, an approach that should be broadly applicable
to dendrimer synthesis using any series of orthogonal coupling
reactions.
Acknowledgment. Funding of this work by the National Institutes
of Health (GM39782) is gratefully acknowledged. F.Z. thanks the
University of Illinois Department of Chemistry for a fellowship.
(19) This represents a general disadvantage of the convergent approach
to dendrimer synthesis. However, the Mitsunobu and Sonogashira reactions
are sterically demanding and were partly chosen as a stringent test of the
orthogonal approach to dendrimer synthesis. Other coupling reactions are
expected to proceed with higher yields and conversions.
(20) Zimmerman, S. C.; Zeng, F.; Reichert, D. E. C.; Kolotuchin, S. V.
Science 1996, 271, 1095-1098.
(21) Leon, J. W.; Fre´chet, J. M. J. Polym. Bull. 1995, 35, 449-455.
Supporting Information Available: Spectral and chromatographic
data for 4-7 and 12-16 (48 pages). Ordering information is given
on any current masthead page.
JA960317S