Segment block dendrimers via diels-alder cycloaddition

Article abstract of DOI:10.1021/ol800553t

(Chemical Equation Presented) Segment block dendrimers consisting of polyester and polyaryl ether dendrons were synthesized using reagent free Diels-Alder cycloaddition reactions. Three generations of furan functionalized polyaryl ether dendrons were reacted with maleimide functionalized polyester dendrons of the same generation to obtain segment block dendrimers in good yields. The thermoreversible nature of these macromolecules was investigated by subjecting them to elevated temperatures in the presence of anthracene as a scavenger diene.

Full text of DOI:10.1021/ol800553t

ORGANIC
LETTERS
2008
Vol. 10, No. 12
2353-2356
Segment Block Dendrimers via
Diels-Alder Cycloaddition
M. Merve Kose, Gulen Yesilbag, and Amitav Sanyal*
Bogazici UniVersity, Chemistry Department, 34342 Bebek, Istanbul, Turkey
amitaV.sanyal@boun.edu.tr
Received March 10, 2008
ABSTRACT
Segment block dendrimers consisting of polyester and polyaryl ether dendrons were synthesized using reagent free Diels-Alder cycloaddition
reactions. Three generations of furan functionalized polyaryl ether dendrons were reacted with maleimide functionalized polyester dendrons
of the same generation to obtain segment block dendrimers in good yields. The thermoreversible nature of these macromolecules was investigated
by subjecting them to elevated temperatures in the presence of anthracene as a scavenger diene.
In the past few decades dendrimers1 have emerged as
attractive nanoscale platforms for various applications in
areas such as drug delivery,2 catalysis,3 formation of enzyme
mimics,4 etc. The fact that they are monodispersed, highly
branched, globular structures without defects have made them
attractive building blocks in macromolecular chemistry.
While the well-defined multivalent construct of the den-
drimer surface itself makes this class of macromolecules
unique, the ability to selectively append different functional
groups onto the surface renders them multifunctional as
opposed to being simply multivalent.
Recent developments have focused on both the efficient
surface functionalization of dendrimers and the synthesis of
dendrimers with orthogonal reactive groups.5 Pioneering
(1) (a) Svenson, S.; Tomalia, D. A. AdV. Drug DeliVery ReV. 2005, 57,
2106–2129. (b) Grayson, S. M.; Fre´chet, J. M. J. Chem. ReV. 2001, 101,
3819–3867. (c) Majoral, J. P.; Caminade, A. M. Chem. ReV. 1999, 99, 845–
880.
(2) (a) Ambade, A. V.; Savariar, E. N.; Thayumanavan, S. Mol. Pharm.
2005, 2, 264–272. (b) Neerman, M. F.; Chen, H. T.; Parrish, A. R.; Simanek,
E. E. Mol. Pharm. 2004, 1, 390–393. (c) Majoros, I. J.; Myc, A.; Thomas,
T.; Mehta, C. B.; Baker, J. R., Jr. Biomacromolecules 2006, 7, 572–579.
(3) (a) Garcia-Martinez, J. C.; Lezutekong, R.; Crooks, R. M. J. Am.
Chem. Soc. 2005, 127, 5097–5103. (b) Crooks, R. M.; Zhao, M.; Sun, L.;
Chechik, V.; Yeung, L. K. Acc. Chem. Res. 2001, 34, 181–190.
(4) (a) Zimmermann, S. C.; Wendland, M. S.; Rakow, N. A.; Zharov,
I.; Suslick, K. S. Nature 2002, 418, 399–403. (b) Tomalia, D. A.; Huang,
B.; Swanson, D. R.; Brothers, H. M., II; Klimash, J. W. Tetrahedron 2003,
59, 3799–3813.
(5) (a) von Baal, I.; Malda, H.; Synowsky, S. A.; von Dangen, J. L. J.;
Hackeng, T. M.; Merkx, M.; Meijer, E. W. Angew. Chem., Int. Ed. 2005,
44, 5052–5057. (b) Malkoch, M.; Schleicher, K.; Drockenmuller, E.;
Hawker, C. J.; Russell, T. P.; Wu, P.; Fokin, V. V. Macromolecules 2005,
38, 3663–3678. (c) Yoon, K.; Goyal, P.; Weck, M. Org. Lett. 2007, 9, 2051–
2054.
10.1021/ol800553t CCC: $40.75
Published on Web 05/20/2008
2008 American Chemical Society

work by Hawker et al. utilized the copper catalyzed [3 + 2]
Huisgen-type cycloaddition reaction between an alkyne and
an azide to obtain orthogonally functionalizable surface block
dendrimers.6 The facile and favorable nature of this cycload-
dition reaction classifies it as a click reaction.7 Such clean
and efficient reactions offer attractive synthetic protocols in
macromolecular chemistry. Steric bulk of the macromolecular
reactants and difficulty in separation from byproducts gener-
ated by undesirable side reactions demand usage of simple,
clean, and high-yielding transformations, attributes offered
by click reactions.8 Another alternative click reaction, the
Diels-Alder cycloaddition between an electron-rich diene
and electron-deficient dienophile has also attracted consider-
able attention in macromolecular synthesis and transforma-
tions.9,10 While the use of facile cycloaddition reactions is
an attractive route for the assembly of reaction components,
cycloreversion under elevated temperatures offers disas-
sembly on demand. Reassembly under mild conditions
provides a repair mechanism of components.11
Scheme 2
.
Divergent Synthesis of Maleimide Functionalized
Dendron
To date, in dendrimer synthesis the Diels-Alder reaction has
been utilized to combine identical dendrons to furnish sym-
metrical dendrimers.12 Our interest to utilize Diels-Alder-based
synthetic strategies in macromolecular synthesis prompted us
to evaluate the cycloaddition reaction toward the synthesis of
unsymmetrical dendrimers. Herein we report the first example
for synthesis of segment block (AB type) dendrimers with
Diels-Alder reaction (Scheme 1). The reaction does not require
dendron 2b was obtained by deprotection of the acetal groups
in 6, followed by treatment of thus-obtained diol with
anhydride monomer 5 and subsequent rDA reaction by
refluxing in toluene. Similar steps were followed to obtain
the desired third-generation dendron.
Scheme 1. General Representation of the Strategy Utilized
Three generations of furan-functionalized polyaryl ether
dendrons were prepared by coupling the acid-functionalized
Fre´chet dendrons14 with furfuryl alcohol in the presence of
DMAP and DCC at ambient temperature. Dendrons were
obtained with 88%, 90%, and 58% yields, respectively
(Scheme 3).
use of metal catalysts and hence the dendrimers formed this
way are free of metal impurities which, when present, may cause
problems if their biological use is intended.
Acetal-protected polyester dendrons were prepared diver-
gently13 starting with a furan-protected N-hydroxypropyl-
maleimide 4. Coupling reaction with the anhydride monomer
5 in presence of 4-(dimethylamino)pyridine (DMAP) pro-
duced 6, which upon refluxing in toluene at 110 °C furnished
the desired dendron 2a containing the reactive maleimide
group at the focal point (Scheme 2). Second-generation
Scheme 3. Core Modification of Fre´chet Dendrons
(6) (a) Wu, P.; Malkoch, M.; Hunt, J. N.; Vestberg, R.; Kaltgrad, E.;
Finn, M. G.; Fokin, V. V.; Sharpless, K. B.; Hawker, C. J. Chem. Commun.
2005, 5775–5777. (b) Lee, J. W.; Kim, B. K. Bull. Korean Chem. Soc.
2005, 26, 658–660.
(7) (a) Rostovtsev, V. V.; Green, L. G.; Fokin, V. V.; Sharpless, K. B.
Angew. Chem., Int. Ed. 2002, 41, 2596–2599. (b) Kolb, H. C.; Finn, M. G.;
Sharpless, K. B. Angew. Chem., Int. Ed. 2001, 41, 2004–2021.
(8) (a) Wu, P.; Feldman, A. K.; Nugent, A. K.; Hawker, C. J.; Scheel,
A.; Voit, B.; Pyun, J.; Fre´chet, J. M. J.; Sharpless, K. B.; Fokin, V. V.
Angew. Chem., Int. Ed. 2004, 43, 3928–3932. (b) Hawker, C. J.; Wooley,
K. L. Science 2005, 309, 1200–1205.
(9) (a) Ilhan, F.; Rotello, V. M. J. Org. Chem. 1999, 64, 1455–1458.
(b) Kim, T. D.; Luo, J.; Ka, J. W.; Hau, S.; Tian, Y.; Shi, Z.; Tucker,
N. M.; Jang, S. H.; Kang, J. W.; Jen, A. K.-Y. AdV. Mater. 2006, 18, 3038–
3042. (c) Voit, B. New J. Chem. 2007, 31, 1139–1151. (d) Goodall, G. W.;
Hayes, W. Chem. Soc. ReV. 2006, 35, 280–312. (e) Wiesler, U.-M.; Mullen,
The reaction of furan-functionalized dendrons 1a-c with
dendrons 2a-c in benzene at 85 °C for 24 h afforded the
K. Chem. Commun. 1999, 2293–2294
.
2354
Org. Lett., Vol. 10, No. 12, 2008

three generations of dendrimers 3a-c in 98%, 76%, and
79%, respectively (Scheme 4). The cycloaddition reactions
Scheme 4. Structures of the Unsymmetrical Dendrimers
Figure 1
dendrimer.
.
1H NMR spectra of 1b and 2b dendrons and 3b
of temperature on exoendo ratios of the formed products, a
series of reactions with first generation dendrons 1a and 2a
were done at rt, 45, 65, and 85 °C for 24 h. The results
suggest that fine-tuning of the reaction temperature plays an
important role for the stereoselectivity of the formed product
and it is possible to obtain pure exo product at 85 °C for the
first generation dendrimers 3a (Figure 2). However it was
were very clean transformations, resulting in desired den-
drimers after column chromatography.
These dendrimers possess a bicyclic furan maleimide
cycloadduct as a core. The Diels-Alder reaction between a
furan and maleimide produces cycloadducts as exo and endo
isomers. The endo/exo selectivity of the reaction was
determined using 1H NMR spectroscopy as described later.
Proton NMR data of the dendrimer shows that the two
dendrons are combined together through a bicyclic core.
Appearance of new proton resonances corresponding to the
bicyclic core at 5.2 and 2.9 ppm and the disappearance of
characteristic peaks belonging to the maleimide and furan
units at the dendron focal points elucidate the structure of
the core (Figure 1).
Figure 2. Effect of reaction temperature on stereochemistry of the
core of dendrimer 3a.
Due to the facile thermoreversibility of the endo products
relative to the exo adducts, a higher reaction temperature
favors formation of exo adducts. In order to investigate effect
not possible to exclusively obtain exo product for the second-
and third-generation dendrimers 3b and 3c. At this point, a
previous literature example was helpful for determining the
peaks in the 1H NMR corresponding to exo/endo isomers.15
For example, in first-generation dendrimer 3a, the benzoic
ester methylene protons in the exo cycloadducts appear as
doublets at 5.11 and 4.65 ppm, whereas for the endo-adducts
(10) (a) Gacal, B.; Durmaz, H.; Tasdelen, M. A.; Hizal, G.; Tunca, U.;
Yagci, Y.; Demirel, A. L. Macromolecules 2006, 39, 5330–5336. (b)
Gheneim, R.; Perez-Berumen, C.; Gandini, A. Macromolecules 2002, 35,
7246–7253. (c) Gousse, C.; Gandini, A.; Hodge, P. Macromolecules 1998,
31, 314–321. (d) Dispinar, T.; Sanyal, R.; Sanyal, A. J. Polym. Sci. Part
A: Polym. Chem. 2007, 45, 4545–4551.
(11) (a) Chen, X.; Dam, M. A.; Ono, K.; Mal, A.; Shen, H.; Nutt, S. R.;
Sheran, K.; Wudl, F. Science 2002, 295, 1698–1702. (b) Chen, X.; Wudl,
F.; Mal, A. K.; Shen, H.; Nutt, S. R. Macromolecules 2003, 36, 1802–
1807.
1
they appear at 5.02 and 4.82 ppm. H NMR spectra of the
products have shown that the second-generation dendrimer
3b was obtained with an exo/endo ratio of (91:9), whereas
the third-generation dendrimer 3c was obtained with an exo/
(12) (a) McElhanon, J. R.; Wheeler, D. R. Org. Lett. 2001, 3, 2681–
2683. (b) Szalai, M. L.; McGrath, D. V.; Wheeler, D. R.; Zifer, T.;
McElhanon, J. R. Macromolecules 2007, 40, 818–823.
(13) Malkoch, M.; Malmstro¨m, E.; Hult, A. Macromolecules 2002, 35,
8307–8314.
(15) Watanabe, M.; Yoshie, N. Polymer 2006, 47, 4946–4952. Also see
the Supporting Information for detailed assignment of exo endo peaks.
(14) Kawa, M.; Fre´chet, J. M. J. Chem. Mater. 1998, 10, 286–296.
Org. Lett., Vol. 10, No. 12, 2008
2355

endo ratio of (87:13). But, thermal treatment, as described
later, allows one to obtain dendrimers with exo bridged cores.
To simplify the access to pure exo isomer of dendrimers
3b and 3c, we added a furan-functionalized Merrifield resin
to scavenge any remaining maleimide dendron that was
difficult to separate from the desired dendrimer using
chromatographic techniques. This thermal treatment of
mixture of endo/exo adducts with the scavenger resin at 50
°C also enables one to exclusively obtain exo bridged
dendrimer. The resulting exo dendrimers were further
characterized by GPC (Figure 3) giving narrow polydispersity
Figure 4.
1H NMR spectra of second-generation dendrimer (3b)
and the retro-Diels-Alder products.
To sum up, a general strategy for the combination of
dendrons to obtain dendrimers in good yield has been
developed using a reagent-free thermal cycloaddition reac-
tion. Further work along these lines to obtain dendron-
polymer conjugates are currently in progress and will be
reported in due course.
Figure 3. GPC results for the dendrimers 3a-c.
values as expected; however, the molecular weights were
far from the exact values due to the globular shape of the
dendrimers.
Acknowledgment. This work was supported by The
Scientific and Technological Research Council of Turkey
(TUBITAK) (105S353) and Bogazici Research Fund
(06HB506). We acknowledge Prof. Dr. Christoph A.
Schalley at the Institut fu¨r Chemie and Biochemie, Freie
Universita¨t Berlin, for kindly providing the HRMS data.
In order to demonstrate the thermoreversibility property
of the dendrimers formed, dendrimer 3b was refluxed in
toluene in the presence of anthracene. Anthracene was added
as a scavenger diene to prevent reassembly of the released
maleimide and furan dendrons.
Cycloaddition with anthracene under these conditions
produces an adduct that is nonreversible. Disappearance of
the peak at 2.94 ppm proves that the dendrimer 3b has
disassembled completely. 1H NMR data shows that the peaks
corresponding to 1b were recovered completely. Furthermore
absence of a singlet at 6.64 ppm and formation of the new
multiplet at 3.16 ppm indicates that maleimide has com-
pletely reacted with the anthracene molecule (Figure 4).
Supporting Information Available: Complete details of
the synthesis and characterizations of the dendrons 1a-c,
2a-c, and dendrimers 3a-c. This material is available free
of charge via the Internet at http://pubs.acs.org.
OL800553T
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Org. Lett., Vol. 10, No. 12, 2008