ChemComm
Cite this: Chem. Commun., 2011, 47, 8955–8957
COMMUNICATION
HYDRAmers: design, synthesis and characterization of different
generation novel Hydra-like dendrons based on multifunctionalized
adamantanew
´ ´
Giuseppe Lamanna,* Julie Russier, Cecilia Menard-Moyon and Alberto Bianco*
Received 24th March 2011, Accepted 8th June 2011
DOI: 10.1039/c1cc11689d
In this communication we present a new synthetic strategy
to different generation Hydra-like dendrons based on tetra-
functionalized adamantane as a building block. The novel
dendrons, which we termed HYDRAmers, possess at the periphery
and at the central core orthogonal protections that can be
exploited for conjugation of targeting ligands, drugs and/or
imaging probes.
effects,6 we have chosen the triphenyladamantane as the
trisubstituted precursor. Triphenyladamantane was synthesized
from cheap and commercially available 1-bromoadamantane
by Friedel–Crafts reaction, and then converted to intermediate
1 by the Schreiner protocol (Scheme 1).5a,7,8
The bromide 1 is a suitable substrate for a Ritter reaction
using acetonitrile.9 This acid-catalyzed step gave the corres-
ponding N-acetylamide 2 in good yield. The generation of the
carboxylic acid functions in the 3-, 5-, 7-positions of adamantane
was carried out by oxidative degradation of the phenyl groups
with RuCl3 and H5IO6 to afford the desired compound 3 in
85% yield as depicted in Scheme 1.10 At this point of the
synthesis, we decided to replace the acetyl group on the amino
function of 3 with a more practical and easy to handle
protecting group, the tert-butoxycarbonyl (Boc) function,
introduced using acidic hydrolysis followed by standard
reaction with Boc2O in the presence of triethylamine and
without any further purification.
In the biomedical field, dendrimers and the so-called
‘‘dendrons’’ (wedge-shaped dendrimer sections)1 are very
promising as the diversity of functionalization brought by
the arborescent structure simultaneously solves the problems
of biocompatibility, toxicity, in vivo stability and specificity.2
Moreover, the chemical and physical properties of most
dendrimers can be tuned by the introduction of appropriate
terminal functional groups as well as internal components.
All these properties make dendrimers and dendrons good
candidates for drug or gene delivery and molecular targets.3
In this context, we wished to investigate dendron structures
based on adamantane because this rigid molecule with a well
defined 3D conformation can bring further advantages to
other proposed dendron structures for studies on multivalent
ligand/receptor interactions.1–4
Tricarboxylic acid 4 was obtained from 1-bromoadamantane
in 6 steps with an overall yield of 23%. This synthesis is easy
scalable, shorter and affords a better overall yield in comparison
to the few examples already reported.5 The obtained multi-
functionalized adamantane is a versatile scaffold with substituents
that allow its further derivatization with linkers of various
lengths and chemical/physical nature to obtain dendrons with
tailored characteristics.
With these purposes in mind, we designed a synthesis of the
unsymmetrical tetrasubstituted adamantane 4 with one amino
and three identical carboxylic acid functions in order to build
the dendron only by formation of amide bonds, which are easy
to form and stable under biological conditions (Scheme 1).
As described by Maison and co-workers,5 the most easy and
scalable synthetic route to get unsymmetrical tetrasubstituted
adamantanes is to start from trisubstituted derivatives.
Considering that substitutions at the adamantane bridgeheads
become more difficult with the number of attached electron-
withdrawing substituents due to statistical and/or electronic
As a first attempt we decided to use methyl-6-aminohexanoate,
a spacer terminated by a methyl ester group, with the purpose
to prepare the 1st generation (G1) dendron 5 possessing
orthogonal protections. The latter was synthesized by coupling
tricarboxylic acid 4, activated in turn with N-(3-dimethyl-
aminopropyl)-N0-ethylcarbodiimide hydrochloride (EDCI)
and 1-hydroxybenzotriazole (HOBt), to the hexanoate derivative
(Scheme 1). In the following step of the synthesis, a selective
deprotection of the Boc-amino and ester groups took place,
affording under acidic and alkaline conditions, respectively,
the necessary key building blocks 6 and 7 for the development
of the arborescent structure (Scheme 2). We were delighted to
observe that the coupling between the amine 6 and the triacid
7 gave the new 2nd generation (G2) Hydra-like dendron 8 in
very good yield. These results were supported by the character-
ization of compound 8 by NMR, FT-IR, mass spectrometry
and elemental analysis (Fig. 1; see also ESIw).
´
CNRS, Institut de Biologie Moleculaire et Cellulaire,
Laboratoire d’Immunologie et Chimie The´rapeutiques,
´
15 Rue Rene Descartes, 67084 Strasbourg, France.
E-mail: a.bianco@ibmc-cnrs.unistra.fr, g.lamanna@ibmc-cnrs.unistra.fr;
Fax: +33 388 610680; Tel: +33 388 417088
w Electronic supplementary information (ESI) available: Experimental
procedures, data characterization of new compounds 2–11, and
cytotoxicity tests. See DOI: 10.1039/c1cc11689d
c
This journal is The Royal Society of Chemistry 2011
Chem. Commun., 2011, 47, 8955–8957 8955