Convergent synthesis of dendrimers via the passerini three-component reaction

Article abstract of DOI:10.1021/ol301263v

Tuning properties by programming the surface functional group composition of surface-block dendrimers has been limited to dendrimers with only two types of surface functionality (i.e., surface-diblock dendrimers). The Passerini reaction provides dendrimer

Full text of DOI:10.1021/ol301263v

ORGANIC
LETTERS
2012
Vol. 14, No. 13
3292–3295
Convergent Synthesis of Dendrimers via
the Passerini Three-Component Reaction
Jo-Ann Jee, Lauren A. Spagnuolo, and Jonathan G. Rudick*
Department of Chemistry, Stony Brook University, Stony Brook, New York
11794-3400, United States
jon.rudick@stonybrook.edu
Received May 8, 2012
ABSTRACT
Tuning properties by programming the surface functional group composition of surface-block dendrimers has been limited to dendrimers with
only two types of surface functionality (i.e., surface-diblock dendrimers). The Passerini reaction provides dendrimer products from precursor
dendrons in reasonable yields. This proof-of-principle experiment opens the door to making surface-triblock dendrimers.
Dendrimers are highly branched, globular, and mono-
disperse macromolecules whose physical and chemical
properties are governed by the surface functional groups.1
Strategiestoselectivelytunethesurface groupcomposition
of dendrimers present opportunities in supramolecular
materials1dꢀf and nanomedicine.1f,g,2 Surface-block
dendrimers,3 which contain clusters of functional groups
that are different from the other surface groups (Figure 1),
offer tailored physical properties4 and orthogonal reactiv-
ity for subsequent modification of the dendrimers.5 Sur-
face-diblock dendrimers (Figure 1) are sometimes referred
to as Janus-type dendrimers,6 bow-tie dendrimers,5 or
codendrimers.7 Unanticipated liquid crystal mesophases,8
vesicular self-assemblies for potential drug delivery,7,9
soluble drug delivery vehicles,5,10 organogels,11 and com-
plex interfacial assemblies12 have been obtained from
(7) Yang, M.; Wang, W.; Yuan, F.; Zhang, X.; Li, J.; Liang, F.; He,
B.; Minch, B.; Wegner, G. J. Am. Chem. Soc. 2005, 127, 15107–15111.
(8) (a) Percec, V.; Imam, M. R.; Bera, T. K.; Balagurusamy, V. S. K.;
Peterca, M.; Heiney, P. A. Angew. Chem., Int. Ed. 2005, 44, 4739–4745.
(b) Yuan, F.; Wang, W.; Yang, M.; Zhang, X.; Li, J.; Li, H.; He, B.;
Minch, B.; Lieser, G.; Wegner, G. Macromolecules 2006, 39, 3982–3985.
(c) Bury, I.; Heinrich, B.; Bourgogne, C.; Guillon, D.; Donnio, B.
Chem.;Eur. J. 2006, 12, 8396–8413. (d) Choi, J.-W.; Ryu, M.-H.;
Lee, E.; Cho, B.-K. Chem.;Eur. J. 2010, 16, 9006–9009. (e) Choi,
J.-W.; Cho, B.-K. Soft Matter 2011, 7, 4045–4049. (f) Lenoble, J.;
Campidelli, S.; Maringa, N.; Donnio, B.; Guillon, D.; Yevlampieva,
N.; Deschenaux, R. J. Am. Chem. Soc. 2007, 129, 9941–9952.
(9) (a) Luman, N. R.; Grinstaff, M. W. Org. Lett. 2005, 7, 4863–4866.
(b) Percec, V.; Wilson, D. A.; Leowanawat, P.; Wilson, C. J.; Hughes,
A. D.; Kaucher, M. S.; Hammer, D. A.; Levine, D. H.; Kim, A. J.; Bates,
F. S.; Davis, K. P.; Lodge, T. P.; Klein, M. L.; DeVane, R. H.; Aqad, E.;
Rosen, B. M.; Argintaru, A. O.; Sienkowska, M. J.; Rissanen, K.;
Nummelin, S.; Ropponen, J. Science 2010, 328, 1009–1014. (c) Peterca,
M.; Percec, V.; Leowanawat, P.; Bertin, A. J. Am. Chem. Soc. 2011, 133,
20507–20520.
(1) (a) Bosman, A. W.; Janssen, H. M.; Meijer, E. W. Chem. Rev.
ꢀ
1999, 99, 1665–1688. (b) Grayson, S. M.; Frechet, J. M. J. Chem. Rev.
2001, 101, 3819–3867. (c) Tomalia, D. A. Soft Matter 2009, 6, 456–474.
(d) Donnio, B.; Buathong, S.; Bury, I.; Guillon, D. Chem. Soc. Rev. 2007,
36, 1495–1513. (e) Rosen, B. M.; Wilson, C. J.; Wilson, D. A.; Peterca,
M.; Imam, M. R.; Percec, V. Chem. Rev. 2009, 109, 6275–6540. (f)
Astruc, D.; Boisselier, E.; Ornelas, C. Chem. Rev. 2010, 110, 1857–1959.
(g) Mintzer, M. A.; Grinstaff, M. W. Chem. Soc. Rev. 2011, 40, 173–190.
(2) Algar, W. R.; Prassuhn, D. E.; Stewart, M. H.; Jennings, T. L.;
Blanco-Canosa, J. B.; Dawson, P. E.; Medintz, I. L. Bioconjugate Chem.
2011, 22, 825–858.
ꢀ
(3) Wooley, K. L.; Hawker, C. J.; Frechet, J. M. J. J. Chem. Soc.,
Perkin Trans. 1 1991, 1059–1076.
(4) Hawker, C. J.; Wooley, K. L.; Frechet, J. M. J. J. Chem. Soc.,
Perkin Trans. 1 1993, 1287–1297.
ꢀ
(10) (a) Gillies, E. R.; Frechet, J. M. J. Drug Discovery Today 2005,
ꢀ
ꢀ
10, 35–43. (b) Gillies, E. R.; Frechet, J. M. J. J. Org. Chem. 2004, 69, 46–
53. (c) Lee, C. C.; Cramer, A. T.; Szoka, F. C.; Frechet, J. M. J.
ꢀ
ꢀ
(5) Gillies, E. R.; Frechet, J. M. J. J. Am. Chem. Soc. 2002, 124,
14137–14146.
Bioconjugate Chem. 2006, 17, 1364–1368. (d) Lee, C. C.; Gillies, E. R.;
Fox, M. E.; Guillaudeu, S. J.; Frechet, J. M. J.; Dy, E. E.; Szoka, F. C.
ꢀ
(6) Saez, I. M.; Goodby, J. W. Chem.;Eur. J. 2003, 9, 4869–4877.
Proc. Natl. Acad. Sci. U.S.A. 2006, 106, 16649–16654.
r
10.1021/ol301263v
Published on Web 06/15/2012
2012 American Chemical Society

surface-diblock dendrimers. Surface-block dendrimers
having more than two different clusters of surface groups
(e.g., surface-triblock dendrimers (Figure 1)) remain an
unresolved synthetic challenge. Herein, we describe the
convergent synthesis of dendrimers via the Passerini three-
component reaction.13,14 This proof-of-principle experi-
ment establishes a strategy by which surface-triblock
dendrimers can be synthesized.
reaction,13 are established reactions by which three or
more components are combined in a single operation.14
The Passerini reaction is a high fidelity reaction suitable for
polymer synthesis17 and divergent synthesis of dendrimers.18
The Passerini reaction opens the door to surface-diblock
dendrimer compositions not possible via methods described
above and, most importantly, a route to surface-triblock
dendrimers.
Scheme 1. Synthesis of the Alcohol Precursors of the Passerini
Reaction Components
Figure 1. Surface group composition of dendrimer architectures.
Symmetry designed to facilitate the synthesis of dendri-
mers is the Achilles’ heel when synthesizing surface-block
dendrimers. Maximizing the number of equivalent reaction
sites per molecule through symmetry minimizes the number
of synthetic steps required to obtain high molecular weight
and large diameter dendrimers. Synthesis of surface-block
dendrimers by sequential addition of different dendrons to a
symmetric core becomes increasingly laborious as the va-
lency of the core increases (e.g., divalent to trivalent), even
when large excesses of reagents are used.3,4 Difficulty
separating mixtures of dendritic products is a significant
liability for these linear reaction sequences. Stoichiometric
reaction conditions conserve valuable dendritic intermedi-
ates and can be combined with high-dilution techniques that
suppress formation of unwanted byproducts.6 Matching the
symmetry of the core molecule to that of the desired surface-
block dendrimer has yielded efficient syntheses of surface-
diblock dendrimers.8d,15 Nonetheless, coupling of two den-
drons bearing complementary apex functional groups16
remains the most heavily exploited strategy by which to
prepare surface-diblock dendrimers.7,8,16
1,3-Propanediol dendrons were selected as a representa-
tive case study for the convergent synthesis of dendrimers
culminating in a Passerini reaction. The dendrons were
synthesized in a convergent manner following the strategy
ꢀ
19
introduced by Frechet and co-workers. We employed
modified literature procedures for the synthesis of second-
generation dendrons containing either benzyl20 or linear
alkyl21 peripheral groups (Scheme 1). In refluxing THF,
methallyl dichloride was treated with an excess of either
benzyl alcohol or 1-decanol in the presence of NaH.
Extended reaction times were encountered when decanol
was the nucleophile source. Reaction times were reduced
from 22 to 5 h when 15-crown-5 was added as a catalyst.
Even under these conditions, careful chromatographic
separation was required to remove small amounts of the
monoalkylated intermediate. The resulting first-generation
alkenes (1a and 1b) were subjected to hydroboration with
9-BBN followed by oxidation by H2O2 in the presence of
NaOH. The first-generation alcohols (2a and 2b) provided
the nucleophile source in a subsequent Williamson ether
synthesis with methallyl dichloride in the presence of NaH
Given the widespread adoption of synthesis methods
that directly couple dendrons, we were intrigued by the
prospect of employing multicomponent reactions in the
final step of a convergent synthesis of a dendrimer. Iso-
cyanide multicomponent reactions, such as the Passerini
(11) Yang, M.; Zhang, Z.; Yuan, F.; Wang, W.; Hess, S.; Lienkamp,
K.; Lieberwirth, I.; Wegner, G. Chem.;Eur. J. 2008, 14, 3330–3337.
(12) (a) Yuan, F.; Zhang, X.; Yang, M.; Wang, W.; Minch, B.; Lieser,
G.; Wegner, G. Soft Matter 2007, 3, 1372–1376. (b) Yang, M.; Wang,
W.; Lieberwirth, I.; Wegner, G. J. Am. Chem. Soc. 2009, 131, 6283–6292.
(c) Bury, I.; Donnio, B.; Gallani, J.-L.; Guillon, D. Langmuir 2007, 23,
619–625. (d) Maierhofer, A. P.; Brettreich, M.; Burghardt, S.;
Vostrowsky, O.; Hirsch, A.; Langridge, S.; Bayerl, T. M. Langmuir
ꢀ
(17) Kreye, O.; Toth, T.; Meier, M. R. J. Am. Chem. Soc. 2011, 133,
1790–1792.
(18) Wessjohann, L. A.; Henze, M.; Kreye, O.; Rivera, D. G. WO
Patent 134,607, 2011.
(19) (a) Jayaraman, M.; Frechet, J. M. J. J. Am. Chem. Soc. 1998,
120, 12996–12997. (b) Grayson, S. M.; Jayaraman, M.; Frechet, J. M. J.
ꢀ
€
2000, 16, 8884–8891. (e) Brettreich, M.; Burghardt, S.; Bottcher, C.;
ꢀ
Bayerl, S.; Hirsch, A. Angew. Chem., Int. Ed. 2000, 39, 1845–1848.
(13) Passerini, M. Gazz. Chim. Ital. 1921, 51, 181–188.
ꢀ
Chem. Commun. 1999, 1329–1330. (c) Grayson, S. M.; Frechet, J. M. J.
J. Am. Chem. Soc. 2000, 122, 10335–10344.
(20) Cai, C.; Yam, C. M.; Xiao, Z.; Gu, J. U.S. Patent 7,247,384,
2003.
€
(14) Domling, A. Chem. Rev. 2006, 106, 17–89.
(15) (a) Ropponen, J.; Nummelin, S.; Rissanen, K. Org. Lett. 2004, 6,
2495–2497. (b) Ornelas, C.; Weck, M. Chem. Commun. 2009, 5710–5712.
(16) Aoi, K.; Itoh, K.; Okada, M. Macromolecules 1997, 30, 8072–
8074.
(21) Cho, B.-K.; Jain, A.; Nieberle, J.; Mahajan, S.; Wiesner, U.;
€
€
Gruner, S. M.; Turk, S.; Rader, H. J. Macromolecules 2004, 37, 4227–
4234.
Org. Lett., Vol. 14, No. 13, 2012
3293

and 15-crown-5. Subjecting the second-generation alkenes
(3a and 3b) to hydroborationꢀoxidation provided the
corresponding alcohols (4a and 4b) from which the Passer-
ini reaction components were derived.
The dendritic components 8, 9, and 10 react to yield the
anticipated Passerini reaction product.13 We obtained
dendrimer 11 when the reaction was performed neat or
in THF solution (Scheme 4). The reaction was difficult to
1
monitor by H NMR spectroscopy because signals over-
lap, but thin layer chromatography (TLC) provided suffi-
cient evidence for the disappearance of starting materials.
No other intermediates or byproducts were observed from
TLC of the reaction mixture. The product dendrimer was
isolated in 60% yield from column chromatography.
Scheme 2. Synthesis of the Isocyanide Passerini Reaction Component
Scheme 4. Passerini Reaction Between Dendron Components
Isocyanide component 8 was prepared from the second-
generation alcohol 4a (Scheme 2). Alcohol 4a was trans-
formed to the amine 7 in a manner similar to that reported
by Cho and co-workers.22 Alcohol 4a was converted to the
corresponding sulfonate 5 when treated with mesyl chlor-
ide and NEt3. Nucleophilic substitution of the mesylate
with azide was achieved in DMF at 125 °C. The azide 6 was
reduced to the amine 7 under Staudinger conditions.23 The
dendritic amine 7 was converted to the corresponding
formamide in refluxing propyl formate, and the forma-
mide intermediate was dehydrated to the isocyanide 8 by
treatment with PPh3, CCl4, and NEt3.24
The aldehyde and carboxylic acid components 9 and 10
were prepared from the second-generation dendron 4b
(Scheme 3). Oxidation of the alcohol to the aldehyde 9
with PCC in CH2Cl2 was accomplished in satisfactory
yields. Upon storage, the aldehyde 9 undergoes further
reaction to yield a higher molecular weight impurity that
cannot be removed by chromatography on SiO2. Oxida-
tion of 4b with PDC in DMF25 did not yield 10. However,
oxidation of aldehyde 9 to carboxylic acid 10 by NaClO2
under phase transfer conditions was successful.
Figure 2. MALDI-TOF Spectra of the component dendrons
and the Passerini dendrimer 11.
Evidence for the identity of the dendrimer was obtained
from MALDI-TOF mass spectrometry and elemental
analysis. A single mass peak above m/z 1000 is observed
in the MALDI-TOF spectrum (Figure 2). The mass peak
at m/z 2459.6 corresponds to the expected mass for the
[M þ Ag]þ ion. Elemental analysis of the dendrimer was
also consistent with the expected molecular formula
(see Supporting Information).
Scheme 3. Synthesis of the Aldehyde and Carboxylic Acid
Passerini Reaction Components
Resonances unique to the dendrimer product of the
Passerini reaction were observed in both 1H and 13C
NMR spectra. Figure 3 presents portions of the 1H
NMR spectra for the components 8, 9, and 10 and for
dendrimer 11 in CDCl3. A resonance for the R-acyloxya-
mide R-H (c) is observed as a doublet at δ 5.34 ppm. The
methine proton resonances of the 1,3-propanediol den-
drons provide further evidence that the product dendrimer
has incorporated one of each of the three component
(22) Chung, Y.-W.; Lee, J.-K.; Zin, W.-C.; Cho, B.-K. J. Am. Chem.
Soc. 2008, 130, 7139–7147.
(23) Staudinger, H.; Meyer, J. Helv. Chim. Acta 1919, 2, 635–646.
(24) Amato, F.; Marcaccini, S. Org. Synth. 2005, 82, 18–21.
(25) Corey, E. J.; Schmidt, G. Tetrahedron Lett. 1979, 20, 399–402.
3294
Org. Lett., Vol. 14, No. 13, 2012

dendrons. Resonances for the outermost, first-generation
layer of methine protons (a, a0, and a00) at δ 2.22 ppm and δ
2.09 ppm in 11 are essentially unchanged relative to the
component dendrons 8 (δ 2.22 ppm), 9 (δ 2.11 ppm), and
10 (δ 2.15 ppm). An upfield shift of the aldehyde R-H
methine resonance (b0) from δ 2.73ppm in 10 to δ 2.64ppm
in dendrimer 11 is consistent with reduction of the alde-
hyde carbonyl. A small downfield shift of the acid R-H
methine resonance (b00) from δ 2.91 ppm in 9 to δ 2.96 ppm
in dendrimer 11 is consistent with the apex functional
group transformation to an ester. The second-generation
methine resonance (b) of the isocyanide component is
shifted upfield from δ 2.12 ppm in 8 to δ 1.98 ppm in 11.
From these chemical shifts in CDCl3 and relative integra-
tion of the peripheral methyl groups, peripheral benzyl
groups, and R-acyloxyamide R-H resonances of 11 mea-
sured in CCl4 solution,26 we conclude that the dendrimer
has the structure and composition expected from the
Passerini reaction.
narrow molecular weight distributions reportedinFigure4
indicate the purity of each compound.
Figure 4. Elution profiles and molecular weight distributions
(Mw/Mn) of the component dendrons and the Passerini reaction
product obtained from GPC in THF.
Isocyanide multicomponent reactions of dendrons yield
dendrimers having precisely controlled surface group
compositions. In our proof-of-concept experiment, the
dendrons and dendrimer were prepared following the
convergent strategy developed for 1,3-propanediol
dendrons. We expect that this Passerini reaction can be
extended to dendrons based on other types of branched
repeating units because of the benign reaction conditions.
Slower reaction kinetics at higher generations, and dimin-
ishing yields attributed tosteric congestion at the periphery
of the dendrimer will affect the scope of this strategy. The
advantage of this multicomponent reaction to synthesize
dendrimers is that surface-triblock dendrimers, having
three distinct clusters of surface functional groups, can
be prepared in a single synthetic transformation. Surface-
triblock dendrimers are an unprecedented dendritic archi-
tecture. The Passerini reaction described herein shows
the feasibility of accessing libraries of surface-triblock
dendrimers.
Figure 3. Partial 1H NMR spectra of the Passerini reaction
components (a) 8, (b) 9, (c) 10, and (d) product 11 in CDCl3.
Gel permeation chromatography (GPC) provides in-
sight to the purity of dendrimer 11 because the dendrimer
issignificantlylargerthaneachofthe componentdendrons
(i.e., 8, 9, and 10). Figure 4 compares chromatograms of 8,
9, 10, and 11. Peak retention times reflect the expected size
differences. Dendron 8, which has peripheral benzyl
groups, is smaller than dendrons bearing peripheral decyl
chains (i.e., 9 and 10). Dendrimer 11 elutes faster than each
of the components. There is no indication of smaller
dendrimers or dendrons in any of the chromatograms.
The number-average molecular weight (Mn) and the
molecular weight distribution (Mw/Mn) for 8, 9, 10, and
11 were determined relative to polystyrene standards. The
Acknowledgment. This work was supported by funding
from Stony Brook University to J.G.R. and a Department
of Education GAANN Fellowship to L.A.S. We also
thank Prof. Francis Johnson (Stony Brook University)
for helpful suggestions.
Supporting Information Available. Detailed synthetic
procedures and characterization data. This material is avail-
able free of charge via the Internet at http://pubs.acs.org.
(26) Overlap of the residual CHCl3 resonance with the aromatic
protons prevented integration of the complete 1H NMR spectrum
recorded in CDCl3. Spectra recorded in solventsthat allowed integration
of the full spectrum are reported in the Supporting Information.
The authors declare no competing financial interest.
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