Synthesis of a new tricyclic tetraazatriacetic acid as ligand for gadolinium(III)

Article abstract of DOI:10.1016/j.tetlet.2004.11.133

Polyazapolycarboxylic acids are known to be efficient ligands for the development of gadolinium-based contrast agents used in magnetic resonance imaging (MRI). Given that rigidification of the ligand structure seems to be an important structural parameter

Full text of DOI:10.1016/j.tetlet.2004.11.133

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 611–613
Synthesis of a new tricyclic tetraazatriacetic acid as ligand
for gadolinium(III)
a
a
a
´ ´
Fabienne Dioury, Emmanuelle Guene, Aurore Di Scala-Roulleau,
Clotilde Ferroud,a,* Alain Guya and Marc Portb
a
´
Laboratoire de Chimie Organique UMR CNRS 7084, Case 303, Conservatoire national des arts et metiers,
´
2 rue Conte, 75003 Paris, France
bGuerbet, Centre de Recherche, BP 50400, 95943 Roissy CdG Cedex, France
Received 15 October 2004; revised 24 November 2004; accepted 26 November 2004
Available online 10 December 2004
Abstract—Polyazapolycarboxylic acids are known to be efficient ligands for the development of gadolinium-based contrast agents
used in magnetic resonance imaging (MRI). Given that rigidification of the ligand structure seems to be an important structural
parameter to increase the relaxivity of the corresponding gadolinium complex, we have synthesized a new tricyclic tetraazatriacetate
ligand from commercially available trans-2-aminocyclohexanol. In the synthetic routes described here, the 2-nitrobenzenesulfona-
mide chemistry was used to selectively functionalize the polyamine precursors.
Ó 2004 Elsevier Ltd. All rights reserved.
OH
OH
O
O
The majority of paramagnetic contrast agents used for
magnetic resonance imaging (MRI) diagnoses are com-
plexes of gadolinium.1 The contrast enhancement is
due to the ability of the paramagnetic Gd3+ cation to
shorten the longitudinal (T1) and transversal (T2) relax-
ation times of the water protons in the surrounding tis-
sues. The effectiveness of a gadolinium chelate as MRI
contrast agent is usually assessed in vitro by measuring
the corresponding relaxivities r1 and r2, defined as the
longitudinal and transversal, respectively, relaxation
rates for a millimolar solution of complex.
O
O
O
N
N
N
N
HO
OH
N
N
O
N
OH
HO
OH
OH
O
O
O
OH
DTPA ligand
DOTA ligand
[Gd-DTPA]2- (MagnevistTM
)
[Gd-DOTA]- (DotaremTM
)
r1 = 4.3 mM-1.s-1
r1 = 4.2 mM-1.s-1
Figure 1. Ligands of some routinely used gadolinium-based contrast
agents for MRI; relaxivity of the corresponding complexes (20 MHz,
25 °C)2.
Gadolinium-based contrast agents routinely used for
clinical diagnosis involve linear (DTPA and derivatives)
or cyclic (DOTA and derivatives) polyazapolycarboxylic
acid ligands with longitudinal relaxivities ranging from
3.5 to 5 sꢀ1 mMꢀ1 (Fig. 1).2 Despite such, substances en-
joy widespread use in clinical applications, there, how-
ever, remains a need for new compounds of improved
performances in terms of relaxivity as well as targeting.
Among the structural parameters that influence relaxiv-
ity and, consequently, efficacy of gadolinium-based con-
trast agents, it had been postulated that an increased
rigidity of the chelate structure would be favorable to
an increased longitudinal relaxivity.3,4 Moreover, to be
clinically relevant agents, the new compounds need to
be of sufficient stability to avoid the toxicity of free gad-
olinium together with the toxicity of the ligand free of
ion. This means that both kinetic and thermodynamic
stabilities are important, in addition to selectivity to
avoid transmetallation with endogenic cations. Consid-
ering the thermodynamic stability of gadolinium che-
lates used in clinical practice, a constant of 1017
appeared to be a minimum requirement.
Keywords: Polyazapolycarboxylic acid; Macrocyclic ligand; Gadolin-
ium; Contrast agent; MRI; 2-Nitrobenzene sulfonamide; Functional-
ized polyamine.
*
Corresponding author. Tel.: +33
142710534; e-mail: ferroud@cnam.fr
0 140272402; fax: +33 0
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.11.133

612
F. Dioury et al. / Tetrahedron Letters 46 (2005) 611–613
An efficient synthetic method was established to prepare
the activated aziridine 5 from the racemic form of trans-
2-aminocyclohexanol 2. Indeed, not only this method
does not require the purification of the two amino-alco-
hol derivatives 3 and 4 but also it affords a crude form of
the target aziridine 5 sufficiently pure to be involved as
such in the next step. At last, this process allows the
extension to large-scale preparations (up to 60 mmol)
of the versatile aziridine 5 that proved to be stable dur-
ing a few months at room temperature.
N
N
N
N
HO2C
CO2H
HO2C
CO2H
N
N
N
N
(
)
n
(
)
n
CO2H
CO2H
n = 1 PCTA12 ligand
n = 2 PCTA14 ligand
rac-1
Gd-PCTA12
r1 = 6.9 mM-1.s-1 (20 MHz, 25 ˚C)
Figure 2.
By reaction with a stoichiometric amount of 2-nitro-
benzenesulfonyl chloride in the presence of sodium
hydrogencarbonate, the trans-2-aminocyclohexanol
hydrochloride 2 was chemoselectively N-sulfonylated
to afford the sulfonamide 3 in 98% yield by spontaneous
crystallization from the reaction medium. Subsequent
activation of the hydroxyl function was chemoselectively
realized by reaction with a stoichiometric amount of
methanesulfonyl chloride in the presence of triethyl-
amine. The crude mesylate 3 obtained in 75% yield then
afforded quantitative aziridination in the presence of
potassium carbonate.
The PCTA12 ligand (Fig. 2) was reported to form a sta-
ble Gd3+ complex (logK = 20.8)5 with an improved lon-
gitudinal relaxivity (r1 = 6.9 mMꢀ1 sꢀ1, 20 MHz, 25 °C)
in comparison with that of gadolinium-based contrast
agents clinically used.2 In the context of a program
aimed at the development of more efficient contrast
agents for MRI diagnoses, we decided to prepare the
constrained PCTA12 derivative 1 (Fig. 2) in which one
ethylene bridge connecting two nitrogen atoms of the
triamine block will be replaced by a cyclohexylene
bridge. In this letter, we report the synthesis of the
new tricyclic polyazapolyacetic acid 1 in its racemic
form.
On the other hand, the sulfonylation of ethylenediamine
6 was effectively controlled by reacting diamine 6 with a
sub-stoichiometric amount of 2-nitrobenzenesulfonyl
chloride. The target monosulfonamide 7 was isolated
as its hydrochloride salt in 88% yield and its crude form
was sufficiently pure to be involved as such in the subse-
quent step.7 When aminosulfonamide 7 was treated with
a stoichiometric amount of tert-butyl bromoacetate in
the presence of triethylamine, chemoselective N-alkyl-
ation of the secondary amine occurred and furnished
compound 8 that was isolated in 50% yield. The ring-
opening of the meso-sulfonylaziridine 5 occurred by
reaction with the previously prepared amine 8 and fur-
nished the expected functionalized triamine 9 in 79%
yield.
Two synthetic routes were envisaged to prepare the
desired compound rac-1. Both of them involve the com-
mon functionalized triamine 9 prepared in a convergent
way from the two commercially available reagents trans-
2-aminocyclohexanol hydrochloride 2 and ethylenedia-
mine 6 (Scheme 1). Moreover, in the routes reported,
the selective regiofunctionalization of the polyamine
backbones was achieved by applying FukuyamaÕs
2-nitrobenzenesulfonamide strategy widely used for the
preparation of secondary amines.6
Starting from triamine 9, the first route envisaged was
analogous to the synthetic ways that led us to prepare
several regioselectively functionalized PCTA12 and
PCTA14 derivatives (Fig. 2).8,9 In this approach, the
2,6-bis(bromomethyl)pyridine was reacted with the
activated triamine 9 in the presence of potassium
carbonate and afforded the corresponding macrocycle
10 in 69% yield. While the conventional methods to
remove 2-nitrobenzenesulfonyl implies a treatment with
thiolate at room temperature,10 the cleavage of the
sulfonamide in macrocycle 10 required to warm the
reaction mixture and led to the desulfonylated product
11 in moderate yield (44%) (Scheme 2). Unfortunately,
the subsequent dialkylation step did not lead to the
exclusive formation of the desired triacetate 12. Indeed,
depending on the nature of the solvent and of the base,
mixtures containing the desired product 12 together
with dialkylated product(s) or tetraalkylated product
were obtained. Given that both mixtures were not sep-
arable by chromatography, we envisaged an alternative
route in which the macrocyclization step would involve
the triamine 14 bearing the three acetate pendant arms
(Scheme 3).11
HCl
NH2
H
H
N
N
a
b
SO2Ar
OH
SO2Ar
SO2Me
O
OH
rac-2
rac-3
rac-4
c
N SO2Ar
5
CO2tBu SO2Ar
SO2Ar
NH
d
e
NH2
HCl
H2N
NH
H2N
N
H
6
7
8
SO2Ar
NH
f
H
8
5
+
N
SO2Ar
N
CO2tBu
rac-9
Scheme 1. Reagents and conditions: Ar = 2-NO2–C6H4 (a) 2-nitro-
benzenesulfonyl chloride, NaHCO3, THF, 0 °C ! rt, overnight, 98%;
(b) methanesulfonyl chloride, Et3N, THF, 0 °C, 30 min, 75%; (c)
K2CO3, CH3CN, 45 °C, 1 h, 100%; (d) 2-nitrobenzenesulfonyl chlo-
ride, THF, 0 °C, 3 h then HCl, 88%; (e) tert-butyl bromoacetate, Et3N,
CH3CN, rt, 15 min, 50%; (f) CH3CN, reflux, overnight, 79%.

F. Dioury et al. / Tetrahedron Letters 46 (2005) 611–613
613
In conclusion, the synthesis of the rigidified pyridine
containing azamacrocycle 1 was achieved in five steps
from activated aziridine 5 and ethylenediamine deriva-
tive 8 in 13% overall yield. The preparation of the corre-
sponding Gd3+-complex has been realized and a
preliminary assay of transmetallation in the presence
of Zn2+ cation, at pH = 7 and at 37 °C, showed a stabil-
ity of the complex equivalent to that of complexes
formed with DTPA and DOTA ligands. This result
encouraged us to pursue the characterization; measure-
ments in order to evaluate the relaxivity of the complex
are in due course.
N
N
N
N
b
a
NH
NH
rac-9
ArSO2
N
N SO2Ar
CO2tBu
CO2tBu
rac-11
rac-10
N
N
tBuO2C
CO2tBu
di-N-alkylated product(s)
or
tetra-N-alkylated product
N
+
c or d
N
CO2tBu
rac-12
Scheme 2. Reagents and conditions: (a) 2,6-bis(bromomethyl)pyri-
dine, K2CO3, N,N-dimethylacetamide, 100 °C, 4 h, 69%; (b) PhSH,
Na2CO3, CH3CN, 50 °C, 1 day, 44%; (c) tert-butyl bromoacetate,
Et3N, THF, 55 °C, 1 day; (d) K2CO3, CH3CN, reflux, 2 h then tert-
butyl bromoacetate, reflux, 40 h.
Acknowledgements
Financial support from Laboratoires Guerbet is grate-
fully acknowledged.
CO2tBu
SO2Ar
CO2tBu
References and notes
CO2tBu
SO2Ar
N
N
NH
b
H
N
a
rac-9
CO2tBu
N
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CO2tBu
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c
d, e
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rac-12
Scheme 3. Reagents and conditions: (a) tert-butyl bromoacetate,
K2CO3, CH3CN, reflux, overnight; 65%; (b) 2-mercaptoethanol,
DBU, CH3CN, rt, 2 h, 52%; (c) 2,6-bis(bromomethyl)pyridine,
Na2CO3, N,N-dimethylformamide, 100 °C, 3 h, 59%; (d) HCl, Et2O,
rt, 6 h then ion-exchange resin chromatography, 80%.
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By using an excess of tert-butyl bromoacetate in the
presence of potassium carbonate, the previously pre-
pared secondary disulfonamide 9 was N-alkylated to
afford the corresponding tertiary compound 13 in 65%
yield. The desulfonylation proceeded smoothly by using
2-mercaptoethanol in the presence of 1,8-diazabicy-
clo[5.4.0]undec-7-ene (DBU)12,13 and led to the func-
tionalized triamine 14 that was involved in the
macrocyclization reaction with 2,6-bis(bromom-
ethyl)pyridine to furnish the desired macrocyclic com-
pound in 59% yield. When treated with anhydrous
hydrochloric acid, the triester 12 was converted to the
target macrocyclic triacetic acid 1 isolated with high
yield (80%).
1H and 13C NMR analyses of compound 1 have been done in D2O;
1H and 13C spectra are complex probably due to the co-existence of
several conformers and/or protonated forms in aqueous solution. IR
(KBr): m = 3409 (broad), 2925, 2850, 1738, 1445, 1405, 1201 cmꢀ1
.
FAB-HRMS: m/z calcd for C21H31N4O6 435.2244, found 435.2235
[M+H]+.