Bisfunctionalized Janus molecules

Article abstract of DOI:10.1021/ol049555f

(Matrix Presented) Bisfunctionalized dendritic multiester molecules were synthesized by combined protection-deprotection and divergent-convergent- divergent sequences in high yields leading to dendritic molecules that combine two functionally different su

Full text of DOI:10.1021/ol049555f

ORGANIC
LETTERS
2004
Vol. 6, No. 15
2495-2497
Bisfunctionalized Janus Molecules
Jarmo Ropponen, Sami Nummelin, and Kari Rissanen*
Nanoscience Center, Department of Chemistry, UniVersity of JyVa¨skyla¨,
P.O.B. 35 FIN-40014, UniVersity of JyVa¨skyla¨, Finland
kari.rissanen@jyu.fi
Received March 10, 2004
ABSTRACT
Bisfunctionalized dendritic multiester molecules were synthesized by combined protection−deprotection and divergent−convergent−divergent
sequences in high yields leading to dendritic molecules that combine two functionally different surfaces, polar aliphatic arborol and nonpolar
gallate ether moieties, resulting in a two-faced Janus molecule.
The growing demand for well-defined and functional materi-
als in nanoscale supramolecular applications has led to a huge
increase in the development of synthetic procedures that
combine architectural control1 and incorporation of functional
groups.2,3 As an answer to these demands, dendrimers and
dendritic compounds offer an appealing solution due to their
unique properties. As dendrimers are monodisperse, highly
branched macromolecules with well-defined three-dimen-
sional structures, they have many properties that differ
significantly from those of corresponding linear polymers.4
Due to the ability to control the synthesis, structure, and
functionality of dendrimers, they have found use in applica-
tions such as catalysis,5 light-harvesting systems,6 molecular
(4) (a) Newkome, G. R.; Moorefield, G. R.; Vo¨gtle, F. Dendrimers and
Dendrons; Wiley-WCH: Weinheim, 2001. (b) Fre´chet, J. M. J.; Tomalia,
D. A. Dendrimers and Other Dendritic Polymers; Wiley-WCH: Chichester,
2001.
(1) (a) Percec, V.; Glodde, M.; Johansson, G.; Balagurusamy, V. S. K.;
Heiney, P. A. Angew. Chem., Int. Ed. 2003, 42, 4338-4342. (b) Percec,
V.; Glodde, M.; Bera, T. K.; Miura, Y.; Shiyanovskaya, I.; Singer, K. D.;
Balagurusamy, V. S. K.; Heiney, P. A.; Schnell, I.; Rapp, A.; Spiess, H.-
W.; Hudson, S. D.; Duan, H. Nature (London) 2002, 419, 384-387. (c)
Percec, V.; Cho, W. D.; Ungar, G.; Yeardley, D. J. P. Angew. Chem., Int.
Ed. 2000, 39, 1598-1602. (d) Ma, Q.; Remsen, E. E.; Kowalewski, T.;
Wooley, K. L. J. Am. Chem. Soc. 2001, 123, 4627-4628.
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H. W. I.; Van Benthem, R. A. T. M.; Meijer, E. W. J. Polym. Sci. Part A:
Polym. Chem. 2001, 39, 3112-3120.
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Reek, J. N. H. Chem. ReV. 2002, 102, 3717-3756. (b) Hecht, S.; Fre´chet,
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Vicinelli, V. Curr. Opin. Chem. Biol. 2003, 7, 657-665. (c) Hahn, U.;
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10.1021/ol049555f CCC: $27.50 © 2004 American Chemical Society
Published on Web 06/22/2004

encapsulation,7 and recently in biomedical applications.8
Traditionally, dendritic compounds are prepared using two
different synthesis concepts, i.e., divergent9 or convergent10
methods, and more recently, mixed methods, e.g., for self-
assembling dendrimers, have emerged.11
Scheme 1. Synthesis of First-Generation Dendrimersa
The modular or mixed synthetic strategy enables combina-
tion of two totally different functionalities into one dendrimer
molecule, e.g., highly polar and highly nonpolar regions are
distributed onto the surface of the dendrimer. The preparation
of low-molecular weight bisfunctionalized “bow-tie”8a or
Janus12 [a Roman god of gates and doors, represented with
a double-faced head] dendrimers utilizes this approach and
opens the door to tailoring of the overall properties of the
dendrimers. The extreme functional differences, the two faces
of Janus, at the outer perimeter of a molecule are especially
needed when self-assembling systems are to be designed and
prepared, as very elegantly demonstrated by Percec et al.13
The synthetic strategy here combines a protection-depro-
tection sequence coupled with alternating divergent-
convergent-divergent methods for formation of the den-
drimer generations. Particular interest was focused on the
use of gallate ether-type monodendrons due to their known
self-assembling properties.13 Coupling these nonpolar mono-
dendrons with a polar aliphatic arborol part creates a family
of bisfunctionalized multiester molecules with possible self-
assembling or, when suitably modified, liquid crystalline
properties.
a Reagents and conditions: (a) DCC, DPTS, CH2Cl2, rt, 20 h;
(b) H2, Pd/C, THF-EtOAc, 6 h; (c) THF-HCl (6 M), rt, 3 h.
The route to the first-generation bisfunctionalized multi-
ester dendritic molecule is shown in Scheme 1.
The core molecule monobenzal-pentaerythritol 1 was
prepared by the method of Issidorides and Gulen14 from
pentaerythritol in 76% yield.
(7) (a) Dykes, G. M.; Smith, D. K.; Seeley, G. J. Angew. Chem., Int.
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Int. Ed. 2001, 40, 74-91. (c) Gorman, C. B.; Smith, J. C. Acc. Chem. Res.
2001, 34, 60-71. (d) Hawker, C. J.; Wooley, K. L.; Fre´chet, J. M. J. J.
Am. Chem. Soc. 1993, 115, 4375-4376.
(8) (a) Gillies, E. R.; Fre´chet, J. M. J. J. Am. Chem. Soc. 2002, 124,
14137-14146. (b) Patri, A. K.; Majoros, I. J.; Baker, J. R. Curr. Opin.
Chem. Biol. 2002, 6, 466-471. (c) Lee, J. H.; Lim, Y.-B.; Choi, J. S.; Lee,
Y.; Kim, T.-I.; Kim, H. J.; Yoon, J. K.; Kim, K.; Park, J.-S. Bioconjugate
Chem. 2003, 14, 1214-1221. (d) Padilla De Jesus, O. L.; Ihre, H. R.; Gagne,
L.; Fre´chet, J. M. J.; Szoka, F. C., Jr. Bioconjugate Chem. 2002, 13, 453-
461. (e) Ihre, H. R.; Padilla De Jesus, O. L.; Szoka, F. C., Jr.; Frechet, J.
M. J. Bioconjugate Chem. 2002, 13, 443-452. (f) D’Emanuele, A.;
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95, 447-453.
(9) (a) Buhleir, W.; Wehner, F. V.; Vo¨gtle, F. Synthesis 1987, 155-
158. (b) Tomalia, D. A.; Baker, H.; Dewald, J. R.; Hall, M.; Kallos, G.;
Martin, S.; Roeck, J.; Ryder, J.; Smith, P. Macromolecules 1986, 19, 2466-
2468. (c) Newkome, G. R.; Yao, Z.; Baker, H.; Gupta, V. K. J. Org. Chem.
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7638-7647. (b) Hawker, C. J.; Fre´chet, J. M. J. J. Chem. Soc., Chem.
Commun. 1990, 1010.
The protected first-generation dendritic molecule 3 was
esterified in dichloromethane by N,N-dicyclohexyl carbodi-
imide (DCC) coupling using 4-(dimethylamino)pyridinium
p-toluenesulfonate (DPTS)15 as a catalyst. After purification
by column chromatography on silica, compound 3 was
obtained in 97% yield. The benzylidene acetal protective
group was removed by catalytic hydrogenolysis in quantita-
tive yield to provide partially unprotected molecule 4. The
first-generation monodendron acids 5-7 were prepared from
the corresponding hydroxybenzoic acid methyl esters with
1-bromododecane in DMF at 60 °C using K2CO3 as a base.
Hydrolysis of the ester group with KOH in refluxing ethanol
gave 5-7 in 95, 98, 95% yields, respectively.16 The gallate
ether monodendrons were then coupled with partly unpro-
tected 4 in the presence of DCC and DPTS. The resulting
acetonide-protected compounds 8-10 were easily separated
from molecule 4 by column chromatography in 57, 86, and
81% yields, respectively. Removal of the acetonide groups
in THF-HCl (6 M) mixture resulted in white solids, which,
after separation by filtration and drying in vacuo, gave the
fully unprotected first-generation compounds, 11-13 in 71,
83, and 92% yields, respectively.
(11) (a) Dykes, G. M.; Smith, D. K. Tetrahedron 2003, 59, 3999-4009.
(b) Zeng, F.; Zimmerman, S. C.; Kolotuchin, S. V.; Reichert, D. E. C.;
Ma, Y. Tetrahedron 2002, 58, 825-843.
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Mori, H.; Mu¨ller, H. E. Prog. Polym. Sci. 2003, 28, 1403-1439. (c) de
Gennes, P.-G. Angew. Chem., Int. Ed. Engl. 1992, 31, 842-845.
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S. K.; Heiney, P. A. Chem. Eur. J. 2003, 9, 921-935. (b) Ungar, G.; Liu,
Y.; Zeng, X.; Percec, V.; Cho, W.-D. Science 2003, 299, 1208-1211. (c)
Percec, V.; Cho, W.-D.; Ungar, G.; Yeardley, D. J. P. Chem. Eur. J. 2002,
8, 2011-2025. (d) Percec, V.; Cho, W.-D.; Ungar, G.; Yeardley, D. J. P.
J. Am. Chem. Soc. 2001, 123, 1302-1315. (e) Percec, V.; Ahn, C.-H.;
Ungar, G.; Yeardley, D. J. P.; Moller, M.; Sheiko, S. S. Nature (London)
1998, 391, 161-164. (f) Percec, V.; Cho, W.-D.; Mosier, P. E.; Ungar, G.;
Yeardley, D. J. P. J. Am. Chem. Soc. 1998, 120, 11061-11070. (g) Hudson,
S. D.; Jung, H.-T.; Percec, V.; Cho, W.-D.; Johansson, G.; Ungar, G.;
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Org. Lett., Vol. 6, No. 15, 2004

2). Compound 11 was coupled with 2 in the presence of
DCC and DPTS. Again, column chromatography was used
to isolate 14 in 93% yield. Compounds 15 and 16 were
prepared in a similar manner and after purification were
obtained in 89 and 12% yields, respectively. The acetonide
protection was removed with a THF-HCl (6 M) mixture.
After the reaction was complete, the mixture was washed
with CH2Cl2 and dried with MgSO4. The evaporation and
drying in vacuo afforded dendrimers 17-19 in 92, 95, and
82% yields, respectively. All compounds were fully char-
Scheme 2. Synthesis of Second-Generation Dendrimersa
1
acterized by H and 13C NMR, and ESI-TOF MS (see
Supporting Information).
We have demonstrated that a protection-deprotection
scheme in combination with a divergent-convergent-
divergent method is a very efficient route to novel bis-
functionalized dendritic multiester molecules with two
faces, viz. Janus. Using this facile modular synthetic method,
we have combined nonpolar aromatic monodendrons with
the aliphatic highly branched multiester molecules. Work
toward higher generation bisfunctionalized Janus dendrimers
and research on their thermal, self-assembling, and liquid
crystalline properties are currently in progress in our labora-
tory.
Acknowledgment. We thank Spectroscopy Laboratory
Technician Reijo Kauppinen for help in running NMR
spectra and Spectroscopy Laboratory Technician Mirja
Lahtipera¨ for running the ESI-TOF MS spectra. The National
Technology Agency (TEKES, Project 40004/01) has finan-
cially supported this work.
a Reagents and conditions: (a) DCC, DPTS, CH2Cl2, rt, 20 h;
(b) THF-HCl (6 M), rt, 3 h.
Supporting Information Available: Details of experi-
mental procedures and characterization of compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
The second-generation bisfunctionalized dendritic mol-
ecules were synthesized using a divergent method (Scheme
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