ORGANIC
LETTERS
2010
Vol. 12, No. 21
4944-4947
Convergent Synthesis of Geometrically
Disassembling Dendrimers using
Cu(I)-Catalyzed C-O Bond Formation
Nathan W. Polaske, Michael L. Szalai, Charles S. Shanahan, and
Dominic V. McGrath*
The UniVersity of Arizona, Department of Chemistry and Biochemistry,
1306 East UniVersity BouleVard, Tucson, Arizona 85721, United States
Received September 1, 2010
ABSTRACT
The convergent synthesis of geometrically degradable dendrimers based on the 2,4-bis(hydroxymethyl)phenol subunit is presented. The key
step of the synthetic scheme involves the CuI/3,4,7,8-tetramethyl-1,10-phenanthroline-catalyzed coupling of aryl iodides and alcohols. The
synthesis and disassembly of these compounds is discussed.
Dendrimers1 are a widely studied class of globular polymeric
materials with applications ranging from nanomaterials2 to
drug delivery.3,4 The ability to control the degradation of
dendrimers has gained much attention in recent years due
to attractive potential applications in nanomedicine and
materials chemistry.5 Of particular interest is the preparation
of geometrically disassembling (a.k.a. self-immolative) den-
drimers3,6 that represent an efficient cleavage process where
multiple disassembly pathways within the dendrimer subunit
are triggered by a single stimulus. Disassembling systems,
both dendritic and polymeric, have been applied to drug
loading and release,7 detectors,8 signal amplifiers,9 and de-
gradable nanoparticles.10 To date, the synthesis of our
geometrically disassembling dendrimers has followed diver-
gent methods. While viable for preparing materials up to
the second-generation,11 complications such as poor solubil-
ity and incomplete reactions at the periphery12 make the
divergent route less desirable for producing higher-generation
dendrimers of suitable purity. Generating large quantities of
these compounds will require convergent synthetic strate-
gies.13 In addition, a convergent strategy for preparing these
disassembling systems would allow the installation of the
trigger moiety at the final stage of the synthesis.
(7) (a) Amir, R. J.; Pessah, N.; Shamis, M.; Shabat, D. Angew. Chem.,
Int. Ed. 2003, 42, 4494. (b) de Groot, F. M. H.; Albrecht, C.; Koekkoek,
R.; Beusker, P. H.; Scheeren, H. W. Angew. Chem., Int. Ed. 2003, 42, 4490.
(c) Erez, R.; Segal, E.; Miller, K.; Satchi-Fainaro, R.; Shabat, D. Bioorg.
Med. Chem. 2009, 17, 4327.
(1) (a) Frechet, J. M. J.; Tomalia, D. A. Dendrimers and Other Dendritic
Polymers; Wiley: New York, 2002. (b) Newkome, G. R.; Moorefield, C. N.;
Vogtle, F. Dendrimers and Dendrons: Concepts, Syntheses, Applications;
VCH: New York, 2001.
(2) (a) Kim, Y.; Mayer, M. F.; Zimmerman, S. C. Angew. Chem., Int.
Ed. 2003, 42, 1121. (b) Zimmerman, S. C.; Quinn, J. R.; Burakowska, E.;
Haag, R. Angew. Chem., Int. Ed. 2007, 46, 8164.
(8) Sella, E.; Shabat, D. Chem. Commun. 2008, 5701.
(9) Sella, E.; Shabat, D. J. Am. Chem. Soc. 2009, 131, 9934.
(10) DeWit, M. A.; Gillies, E. R. J. Am. Chem. Soc. 2009, 131, 18327.
(11) (a) Szalai, M. L.; Kevwitch, R. M.; McGrath, D. V. J. Am. Chem.
Soc. 2003, 125, 15688. (b) Szalai, M. L.; McGrath, D. V. Tetrahedron 2004,
60, 7261.
(3) McGrath, D. V. Mol. Pharmaceutics 2005, 2, 253
.
(4) van Dongen, S. F. M.; de Hoog, H. M.; Peters, R. J. R. W.; Nallani,
M.; Nolte, R. J. M.; van Hest, J. C. M. Chem. ReV. 2009, 109, 6212
(5) Wallraff, G. M.; Hinsberg, W. D. Chem. ReV. 1999, 99, 1801.
(6) Avital-Shmilovici, M.; Shabat, D. Soft Matter 2010, 6, 1073
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(12) Grayson, S. M.; Frechet, J. M. J. Chem. ReV. 2001, 101, 3819.
(13) Hawker, C. J.; Frechet, J. M. J. J. Am. Chem. Soc. 1990, 112, 7638.
.
10.1021/ol102081q 2010 American Chemical Society
Published on Web 10/06/2010