TETRAHEDRON
LETTERS
Tetrahedron Letters 42 (2001) 7033–7036 Pergamon
Synthesis and characterisation of a new podand based on a
calixarene and a -lactam
Adel Ben Salem and Jean-Bernard Regnouf-de-Vains*
GEVSM, UMR 7565 CNRS -UHP, Faculte ´ de Pharmacie, 5, rue Albert Lebrun, F -54001 Nancy Cedex, France
Received 11 July 2001; revised 13 July 2001; accepted 23 July 2001
Abstract—Two penicillin arms have been grafted at the lower rim of the p -tert -butylcalix[4]arene, giving a new kind of podand
which was fully characterised. © 2001 Elsevier Science Ltd. All rights reserved.
The calixarenes have often been employed in recent
years as carriers and spatial organisers of various kinds
of active substituent, displaying properties dealing with
recognition of organic substrates or metallic cations.
Efforts have also been brought to the use of their
specific conformations in order to prepare, notably in
the case of the tensed calix[4]arene, highly ordered and
organised molecular devices.
1
The expectation of
sophisticated properties related to the high degree of
organisation they are able to provide could nevertheless
hide their ability to act as simple carriers, particularly
in the medicinal field. We found that very few reports,
essentially patents, have been devoted to the study of
calixarenes as intrinsically active therapeutic agents,
such as para -sulfonato-, phophonato- or other
hydrophilic analogues, against bacteria, fungi, cancer-
ous cells and viruses,
2
thrombosis,
3
infection by envel-
oped viruses
4
or fibrosic diseases.
5
Some reports are
attached to the study of the ‘old’ Macrocyclon
6
and
analogues in the treatment of tuberculosis and other
mycobacterioses,
7
or to the building of antimicrobial
calixarene-based vancomymin mimics.
8
In order to develop calixarene-based podands shaped as
potent drug dispensers, we initiated a study related to
the grafting of a simple and easily characterisable drug
subunit displaying unambiguous analytical characteris-
tics. Our first molecular target was an antibiotic peni-
cillin grafted in alternate positions of the cone
conformer of the p -tert -butylcalix[4]arene.
The synthetic strategy involved the formation of a
hemi-synthetic penicillin via the formation of an amide
bound between the calixarene platform and the peni-
cillin moiety. The latter was protected at the carboxy
group by a pivaloyloxymethyl ester function, thus giv-
ing a lipophilic prodrug which should liberate the bio-
logically active free acid after hydrolysis by esterases, as
initially developed with the commercial pivmecillinam
and pivampicillin.
9
The choice of the coupling reaction
involved soft conditions in order to avoid probable
degradation of the -lactam ring. Thus, a previously
described controlled peptide-bound formation process
was chosen.
10
The diacid 1 was reacted with N -hydrox-
ysuccinimide and dicyclohexylcarbodiimide in dry
CH
2
Cl
2
to give the corresponding bis-activated ester 2
with a yield of 85%.
11
The penicillin derivative 3 was
prepared as the tosylate salt in the conditions described
by Daehne et al.,
9
Matlin et al.
12
or Ogura et al.,
13
by
reaction of pivaloyloxymethyl chloride and 6-
aminopenicillanic acid.
The last step consisted of the reaction of 2 and 3 in
mild conditions, in CH
2
Cl
2
at rt under argon. The
bis-penicillin podand 4 was obtained with a good
degree of purity (>95%) after chromatography with a
yield of ca. 70%. An analytical sample was obtained
using precise thin-layer preparative chromatography
(Scheme 1).
Positive mode electrospray mass spectrometry confi-
rmed that the desired compound was obtained with a
base peak at 1411.59 a.m.u., attributed to [M+Na]
+
,
while the negative mode gave a base peak at 1387.86
a.m.u., attributed to [M-H]
-
, accompanied by various
fragmentation products.
IR analysis showed the presence of three intense bands:
one at 1693 cm
-1
, which was attributed to the amide
* Corresponding author. Fax: (33)3 83 17 90 57; e-mail: jean-bernard.
regnouf@pharma.u-nancy.fr
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII:S0040-4039(01)01319-3