Synthesis of a new family of protected 1,4,7,10-tetraazacyclododecane-1,4, 7-triacetic acid derivatives with thioctic acid pending arms

Article abstract of DOI:10.1016/j.tetlet.2012.08.150

The synthesis and characterization of a new family of ester protected N-substituted [1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid (H3DO3A) derivatives containing a pendant thioctic acid (α lipoic acid, LA) are reported. These compounds (DO3A^tBu-NLA, DO3A^tBu-NMeNLA, and DO3A^tBu-NEtNLA) are suitable for the functionalization of gold surfaces with rare-earth complexes.

Full text of DOI:10.1016/j.tetlet.2012.08.150

Tetrahedron Letters 53 (2012) 6115–6118
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis of a new family of protected 1,4,7,10-tetraazacyclododecane-1,4,7-
triacetic acid derivatives with thioctic acid pending arms
⇑
Arnaud de la Reberdière, Fabien Lachaud, Françoise Chuburu, Cyril Cadiou, Gilles Lemercier
Université de Reims Champagne-Ardenne, ICMR, UMR CNRS n° 7312, C2POM team, BP 1039, 51687 Reims cedex 2, France
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 4 July 2012
Revised 11 August 2012
Accepted 31 August 2012
Available online 7 September 2012
The synthesis and characterization of a new family of ester protected N-substituted [1,4,7,10-tetraazacy-
clododecane-1,4,7-triacetic acid (H3DO3A) derivatives containing a pendant thioctic acid (a lipoic acid,
LA) are reported. These compounds (DO3AtBu-NLA, DO3AtBu-NMeNLA, and DO3AtBu-NEtNLA) are suit-
able for the functionalization of gold surfaces with rare-earth complexes.
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
1,4,7,10-Tetraazacyclododecane-1,4,7-
triacetic acid derivatives
Lipoic acid
Gold surface functionalization
The coordination of lanthanide ionic centers by chelating,1 and
macrocyclic ligands such as substituted triazacyclononane
(TACN),2 is an important topic in fundamental research and pho-
tonic applications.3 In this field, macrocyclic derivatives based on
1,4,7,10-tetraazacyclododecane (cyclen), and more particularly
1,4,7,10-tetraazacyclododecane-1,4,7,10-tetracetic acid (DOTA)
analogues,4 are among the most widely studied and used ligands
for efficient complexation of Ln3+ ions, and especially stability
and relative inertness5,6 in water.
These lanthanide complexes are archetypal targets, and used as
contrast agents for magnetic resonance imaging (MRI),7 (including
pH mapping method8), as radiopharmaceuticals for diagnosis and
therapy,9 and as one-10 and two-photon11 excited luminescent tags
in biological systems. Some recent papers have reported the graft-
ing of Cu2+ complexes of 1,4,8,11-tetraazacyclotetradecane (cy-
clam)12 macrocycles on porous and mesoporous silica substrates,
and C-substituted-1,4,7,10-tetraazacyclotridecane monolayers on
glass surfaces.13 These new N- or C-substituted macrocyclic plat-
forms are also of interest in the emerging field of nanosciences
for example as chelates in delivery systems for therapy,14 or in
nano-objects for imagery,15 multimodal imaging,16 and in multi-
functional systems (theragnostic).17 To the best of our knowledge,
only a few linear ligands for rare-earth, involving a thiol function,
have been reported (for instance dithiolated diethylenetriamine-
pentaacetic acid, that is, DTDTPA18). Even less examples involving
a macrocyclic unit,19 can be found in the literature, for example in
order to obtain redox-sensitive contrast agents.20 Therefore, we re-
port herein a convenient route for the preparation of DOTA ana-
logues as candidates for the functionalization of gold surfaces
such as nanoparticles. DO3AtBu-NLA, DO3AtBu-NMeNLA, and
DO3AtBu-NEtNLA are shown in Figure 1. The new family of pro-
tected 1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid deriva-
tives (DO3AtBu) contains a terminal dithiol linker (thioctic or
lipoic acid, LA).
a
Ligand DO3AtBu-NEtNLA has been synthesized according to
the route depicted in Scheme 1a after the N-alkylation of 1,4,7-
tris(tert-butoxycarbonylmethyl)-1,4,7,10-tetraazacyclododecane
(DO3AtBu) with bromoethylphthalimide and conversion into the
primary amine via hydrazinolysis according to Ing-Manske proce-
dure,21 a peptidic coupling using N-hydroxysuccinimide/1-ethyl-3-
[3-dimethylaminopropyl]-carbodiimide hydrochloride (NHS/EDC)
with the activated ester LA-NHS (prepared according to a slightly
modified reported procedure22 Scheme 1b). The crude was concen-
trated and purified over a short column of silica using dichloro-
methane as eluent led to DO3AtBu-NEtNLA. Due to the
instability of the aminal formed via hydrazinolysis, this approach
was not applicable to the synthesis of DO3AtBu-NMeNLA and gave
exclusively the parent compound DO3AtBu (Scheme 1). To over-
come this reactivity, the benzotriazole way developed by Katritzky
et al. revealed that a pertinent methodology being an efficient ac-
cess to N-acylaminals.23 The N-(benzotriazol-1-ylmethyl) lipoic
amide obtained by condensation of 1-hydroxymethylbenzotriazole
with lipoic amide (Scheme 1b) reacted with DO3AtBu to give
DO3AtBu-NMeNLA. The well-documented polymerization of lipoic
derivatives24 never occurred when coupling the lipoic moiety to
the macrocyclic unit, even if the high temperature and the acidic
conditions of the condensation with 1-hydroxymethylbenzotriazole
⇑
Corresponding author. Tel.: +33 032 691 3240; fax: +33 032 691 3243.
E-mail address: gilles.lemercier@univ-reims.fr (G. Lemercier).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.08.150

6116
A. de la Reberdière et al. / Tetrahedron Letters 53 (2012) 6115–6118
O
O
O
O
O
O
O
O
N
N
O
N
N
N
O
N
N
N
N
O
O
N
N
O
H
N
O
O
N
O
O
N
S
H
O
O
O
S
O
S
S
S
DO3AtBu-NEtNLA
DO3AtBu-NMeNLA
S
DO3AtBu-NLA,
Figure 1. Molecular structures of macrocyclic ligands DO3AtBu-NLA, DO3AtBu-NMeNLA, and DO3AtBu-NEtNLA.
O
O
O
O
O
O
N
O
O
O
O
O
O
O
O
O
Br
LA-NHS
O
N
N
O
N
N
N
N
N
N
N
N
N
O
N
N
N
(i)
O
(ii)
(i)
HN
N
O
O
O
O
O
N
NH2
O
O
O
O
O
S
S
DO3AtBu-NEtNH2
DO3AtBu
DO3AtBu-NEtNPhth
DO3AtBu-NLA
a
(i)
LA-NH-MeBt
(i)
LA-NHS
O
O
O
O
O
O
N
N
O
N
O
N
N
N
N
O
O
H
N
O
N
N
H
O
S
O
S
O
DO3AtBu -NEtNLA
DO3AtBu-NMeNLA
S
S
HO
N
N
N
b
O
O
O
N
O
O
S
S
S
N
S
S
S
NH2
N
O
N
H
OH
S
S
N
O
(v)
(iv)
(iii)
LA-NHS
LA-NH2
LA-NH-MeBt
Scheme 1. Reagents and conditions: (i) Cs2CO3, CH3CN, 80 °C; (ii) N2H4, MeOH, 65 °C; (iii) NHS/EDC, CH2Cl2, rt; (iv) NH3, 30% in H2O, CH3CN, CH2Cl2, rt; (v) p-toluene–sulfonic
acid (cat), toluene, 100 °C.
could have favored this undesirable side-reaction. Direct use of the
rubbery polymer gave exact results in accordance with the recog-
nized reversibility of the polymerization.25 Ligand DO3AtBu-NLA
was obtained by the nucleophilic attack of DO3AtBu on the acti-
vated ester LA-NHS. General procedure and main characterizations
are reported in the notes.26 Compounds were fully characterized
by 1H, 13C NMR, mass spectrometry, and elemental analysis.
Starting material is DO3AtBu, obtained with 70–80% yield
according to an already published procedure.27 The strategy used
for compound DO3AtBu-NEtNLA, can be generalized to other bro-
moalkylphthalimide in order to increase the length of the alkyl
chain. Synthesis of the versatile DO3AtBu-ethylamine intermediate
compound (DO3AtBu-NEtNH2) bearing a free amine group readily
reactive towards most electrophiles, has already been a part of sev-
eral other synthetic schemes using for example tert-butyloxycar-
bonyl (BOC)28 or carbobenzyloxy (Cbz)29,19a as protecting group
and in the substitution of bis(aminal)-protected cyclen-based bis-
macrocycles,30 and using cyclen and other electrophiles such as
N-chloroacetyl-aza-15-crown-5,31 alkyl-bromides,32 or bromoace-
tonitrile.33 A convenient synthesis of DO3AtBu-NEtNH2 (EtO-ester
analogue) and the corresponding cyclam-based macrocycle was
also reported by Mishra and Chatal.34
A new family of monosubstituted macrocyclic ligands (DO3AtBu)
with anchored thioctic acid moieties as pendant arms, have
been reported. Work is in progress to involve these ligands in
new Ln(III) complexes (Gd3+, Eu3+, Tb3+, Yb3+). This study opens
the route to the functionalization of gold surfaces, allowing a
fine-tuning of the distance between the complex and the metallic
surface. It gives also the opportunity of obtaining Au nanoparticles,
especially for applications in therapy and/or biological imaging.

A. de la Reberdière et al. / Tetrahedron Letters 53 (2012) 6115–6118
6117
26. Materials and methods: All reactions were performed under an argon
atmosphere using standard Schlenk techniques. 1H NMR spectra were
recorded in CDCl3, on a Bruker 250 DPX. Chemical shifts are reported in
delta (d units, expressed in parts per million (ppm). Coupling constants are
given in hertz (Hz), and multiplicity expressed as follows: s for singlet, d for
doublet, t for triplet, b for broad signal and m for a multiplet. High-resolution
mass spectra (HRMS) were obtained with a Micromass Q-TOF electrospray
positive ionization. Typical experimental procedure for:
Acknowledgment
The authors are grateful to ‘École Normale Supérieure de Lyon’
for the thesis Grant allocation to AdlR.
References and notes
Compound DO3AtBu-NEtNPhth: Bromoethylphtalimide (158 mg, 0.65 mmol),
and cesium carbonate (360 mg, 1.10 mmol) were added to
a solution of
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DO3AtBu under argon atmosphere (285 mg, 0.55 mmol) in freshly distilled
acetonitrile (5 mL). The suspension was heated to reflux for 24 h, before being
filtered at room temperature. The yellow filtrate was evaporated under
reduced pressure and 10 mL chloroform was added in order to precipitate
residual inorganic impurities. Evaporation of the solvent afforded DO3AtBu-
NEtNPhth as a clear yellow oil (429 mg, quantitative yield), which was used
without further purification. An analytical sample was obtained after
purification over a short column of silica using dichloromethane/methanol
(92:8) as eluant. 1H NMR (CDCl3) d: 7.73–7.55 (m, 4H), 3.61 (bt, J = 6.0 Hz, 2H),
3.06 (s, 6H), 2.62, 2.53 (m, 18H), 1.30 n (s, 27H); 13C NMR (CDCl3) d: 170.86,
170.82, 168.08, 134.36, 133.61, 132.05, 122.88, 80.36, 56.43, 56.21, 52.61,
52.16, 51.78, 35.66, 28.03. ESI-MS Calcd for C36H58N5O8: m/z = 688.4 (M+H+),
obsd 688.5 (M+H+) and 710.5 (M+Na+); DO3AtBu-NMeNPhth. Bro-
momethylphtalimide (85 mg, 0.35 mmol), sodium iodide (53 mg, 0.56 mmol)
and cesium carbonate (177 mg, 0.54 mmol) were added to
a solution of
DO3AtBu under argon atmosphere (172 mg, 0.33 mmol) in freshly distilled
acetonitrile (5 mL). The suspension was heated to reflux for 24 h, before being
filtered at room temperature. The yellow filtrate was evaporated under
reduced pressure and 10 mL chloroform was added in order to precipitate
residual inorganic impurities. Evaporation of the solvent and addition of 20 mL
of ether led to precipitation of a yellow powder corresponding to the sodium
adduct C35H55N5O8.NaI.H2O (191 mg, 67% yield). 1H NMR (CDCl3) d: 7.82–7.71
(m, 4H), 4.66 (s, 2H), 3.27–2,34 (broad signals overlapping, 22H), 1.48–1,40
(two signals overlapping, 27H); 13C NMR (CDCl3) d: 173.91, 173.30, 169.70,
134.58, 131.69, 123.59, 83.03, 82.73, 57.62, 56.48, 55.69, 53.55, 51.77, 51.15,
48.34, 28.06, 27.88. Anal. Calcd for C35H55N5O8.NaI.H2O: C, 49.94; H, 6.83; N,
8.32. Found: C, 50.13; H, 6.67; N, 8.49.
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Compound DO3AtBu-NEtNH2: To the crude oil of DO3AtBu-NEtNPhth (429 mg)
dissolved in 7 mL MeOH was added hydrazine monohydrate (55 lL,
1.13 mmol). The solution was heated at reflux for 4 h, and the solvent was
evaporated. 20 mL CH2Cl2 was added to the resulting solids and the insoluble
phtalhydrazide impurities were filtered out. The filtrate was washed first with
distilled water (4 Â 10 mL), then with 5 mL of an aqueous solution of KOH 20%
and the organic layer was dried under MgSO4. Evaporation of the solvent under
reduced pressure yielded an amber oil (281 mg, 91%). 1H NMR (CDCl3) d: 3.32–
3.29 (two signals overlapping, 6H), 2.81–2.57 (m, 20H), 1.44 (s, 27H). 13C NMR
(CDCl3) d: 170.98, 80.57, 80.48, 56.28, 52.53, 51.90, 51.75, 39.58, 28.11. Anal.
Calcd for C28H55N5O6.0.25 CHCl3: C, 57.74; H, 9.48; N, 11.92. Found: C, 57.46;
H, 9.45; N, 11.95. ESI-MS: obsd m/z = 558.3 (M+H+).
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Compound DO3AtBu-NEtNLA: Under argon atmosphere potassium carbonate
(143 mg, 1.04 mmol) and LA-NHS (189 mg, 0.62 mmol) were added to
a
solution of DO3AtBu-NEtNH2 (290 mg, 0.52 mmol) in anhydrous acetonitrile
(10 ml). The solution was kept at reflux for 24 h. Then the reaction mixture was
allowed to cool at room temperature and was filtered. The filtrate was
evaporated and purified over a short column of alumina deactivated with
water (5%) using dichloromethane: ethyl acetate as eluent (100:0 to 0:100).
Evaporation of the solvent afforded DO3AtBu-NEtNLA as a clear yellow oil
(322 mg, 83%). 1H NMR (CDCl3) d 3.55(m, 1H), 3.27–3.02 (signals overlapped,
10H), 2.82–2.39 (signals overlapped, 18H) 2.15 (t, J = 7.3 Hz, 2H), 1.89 (m, 1H),
1.65–1.41 (signals overlapped, 33H) 13C NMR (CDCl3) d: 172.88, 170.88, 170.65,
80.99, 57.61, 56.51, 56.13, 52.74, 52.45, 51.94, 40.28, 38.51, 36.23, 34.89, 29.26,
28.30, 25.57. ESI-MS: m/z = 746.46 (M+H+). Anal. Calcd for C15H20N4OS2: C,
53.54; H, 5.99; N, 16.65; S, 19.06. Found: C, 53.66; H, 6.10; N, 16.16; S, 19.39.
Compound LA-NH2: The activated ester LA-NHS (707 mg, 2.53 mmol) was
dissolved in a chloroform/acetonitrile mixture (1:2, 15 mL). Then, ammonia
(30% in water) was added until the appearance of two phases. The
heterogeneous solution was left under vigorous stirring for one hour. After
addition of chloroform (15 mL) the crude product was extracted with water
(2 Â 15 mL) and aqueous solution of KOH (20%). The organic layer was dried
under MgSO4. Subsequent evaporation led to a yellow solid which was oven-
dried. (485 mg, 93%). 1H NMR (CDCl3) d: 5.53 (broad singlet,2H–NH), 3.63–3.52
(m, 1H), 3.24–3.06 (m, 2H), 2,52–2.40 (m, 1H), 2.24 (t, J = 7.4 Hz, 2H), 1.97–1.84
(m, 1H), 1.77–1.41 (m, 6H). 13C NMR (CDCl3) d: 175.21, 56.52, 40.38, 38.62,
35.69, 34.77, 28.97, 25.27. ESI-MS: m/z = 228.0 (M+Na+).
Compound LA-NH-MeBt: (100 mg, 0.49 mmol), benzotriazolemethanol (72 mg,
0.49 mmol) and p-toluenesulfonic acid (10 mg, 0.05 mmol) were stirred for 6 h
at the reflux in 10 mL toluene. The crude product was washed with an aqueous
KOH solution (10%, 5 mL), dried under MgSO4 and, then, cooled overnight.
Filtration and the consecutive solvent evaporation led to 146 mg of the yellow
desired product (89% yield). 1H NMR (CDCl3) d: 8.05–7.35 (m, 4H), 6.11 (d,
J = 6.9 Hz, 2H), 3.53–3.42 (m, 1H), 3.18–3.01 (m, 2H), 2.43–2.31 (m, 1H), 2.25 (t,
J = 7.4 Hz, 2H), 1.87–1.30 m, 7H. 13C NMR (CDCl3) d: 173.39, 128.20, 124.56,
119.69, 111.07, 56.35, 50.90, 40.26, 38.60, 36.09, 34.62, 28.76, 24.96.. Anal.
Calcd for C15H20N4OS2: C, 53.54; H, 5.99; N, 16.65; S, 19.06. Found: C, 53.66; H,
6.10; N, 16.16; S, 19.39; ESI-MS: m/z = 337.1 (M+H+); m/z = 359.1 (M+Na+);
m/z = 695.3 (2M+Na+).
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Smith, W. E.; Faulds, K.; Graham, D. Chem. Commun. 2007, 27, 2811. Purification
was done by precipitation with diethylether and filtration on silica.
23. Katritzky, A. R.; Fali, C. N.; Bao, W.; Qi, M. Synthesis 1998, 1421.
24. Thomas, R. C.; Reed, L. J. J. Am. Chem. Soc. 1956, 78, 6148.
25. (a) US Patent Application 20070055070-novel esters of lipoic acid.; Kisanuki,
A.; Kimpara, Y.; Oikado, Y.; Kado, N.; Matsumoto, M.; Endo, K. J. Polym. Sci., Part
A: Polym. Chem. 2010, 48, 5247.

6118
A. de la Reberdière et al. / Tetrahedron Letters 53 (2012) 6115–6118
Compound DO3AtBu-NMeNLA: DO3AtBu (103 mg, 0.2 mmol), potassium
overlapped, 33H). 13C NMR (CDCl3) d 172.90, 170.95, 170.85, 81.14, 81.03,
80.93, 58.55, 57.24, 56.56, 54.97, 54.64, 53.26, 52.72, 52.64, 52.30, 51.59, 48.03,
45.72, 38.55, 34.91, 32.90, 29.25, 28.31, 25.33. ESI-MS: m/z = 703.5 (M+H+).
Anal. Calcd for C34H62N4O7S2. 0.66 CHCl3: C, 53.20; H, 8.07; N, 7.16; S, 8.19.
Found: C, 53.36; H, 8.28; N, 7.30; S, 8.16.
carbonate (82 mg, 0.6 mmol) and LA-NH-MeBt (100 mg, 0.3 mmol) were
stirred in freshly distilled acetonitrile at reflux for 48 h. Then, after
evaporation, ether (30 mL) was added to the crude which was filtered after
standing around 6 °C overnight. The filtrate was washed with 10% aqueous
KOH solution (30 mL) and dried under MgSO4,. Evaporation of the ethereal
phase led to a yellow oil corresponding to the desired product (with an
estimated molar purity of 85% in mixture with reactant LA-NH-MeBt) 1H NMR
(CDCl3) d: 4.09 (d, J = 5 Hz, 2H) 3.55 (m, 1H), 3.32–3.03 (signals overlapped, 8H)
2.88–2.65 (signals overlapped, 16H) 2.45 (m, 1H), 2.19 (t, J = 7.6 Hz, 2H), 1.90
(m, 1H), 1.69–1.43 (signals overlapped, 33H). 13C NMR (CDCl3) d: 171.36,
171.14, 81.09, 81.01, 80.95, 60.20, 57.49, 57.03, 56.57, 56.52, 52.64, 52.51,
52.35, 52.12, 51.84, 50.96, 47.63, 40.33, 38.57, 36.53, 34.82, 29.14, 28.35, 25.56.
ESI-MS: m/z = 732.2 (M+H+).
27. Jagadish, B.; Brickert-Albrecht, G. L.; Nichol, G. S.; Mash, E. A.; Raghunand, N.
Tetrahedron Lett. 2011, 52, 2058.
28. Mishra, A.; Pfeuffer, J.; Mishra, R.; Engelmann, J. R.; Mishra, A. K.; Ugurbil, K.;
Logothetis, N. K. Bioconjugate Chem. 2006, 17, 773.
9
29. Dhingra, K.; Fouskovà, P.; Angelovski, G.; Maier, M. E.; Logothetis, N. K.; Toth, E.
J. Biol. Inorg. Chem. 2008, 13, 35.
30. (a) Anda, C.; Bencini, A.; Berni, E.; Ciattini, S.; Chuburu, F.; Danesi, A.; Giorgi, C.;
Handel, H.; Le Baccon, M.; Paoletti, P.; Tripier, R.; Turcry, V.; Valtancoli, B. Eur. J.
Inorg. Chem. 2005, 2044; (b) Max-Planck-Gesellschaft zur Foerderung der
Wissenschaften e.V., Patent EP1637524 A1, 2006.
Compound DO3AtBu-NLA:
A
mixture of DO3AtBu (438 mg, 0.85 mmol),
potassium carbonate (235 mg, 1.71 mmol), and LA-NHS (309 mg, 1.02 mmol)
in 15 mL of anhydrous acetonitrile was stirred at room temperature for 24 h.
Then the crude was allowed to cool at room temperature, filtered, and purified
by chromatography over an alumina column using ether/methanol (96:4).
31. (a) Li, C.; Wong, W.-T. Tetrahedron Lett. 2004, 45, 6055; (b) Li, C.; Li, Y.-X.; Law,
G.-L.; Man, K.; Wong, W.-T.; Lei, H. Bioconjugate Chem. 2006, 17, 571.
32. (a) Li, C.; Wong, W.-T. Tetrahedron Lett. 2002, 43, 3217; (b) Duimstra, J. A.;
Femia, F. J.; Maede, T. J. J. Am. Chem. Soc. 2005, 127, 12847.
Evaporation of the solvent afforded DO3AtBu-NLA as
a
clear yellow oil
33. Mishra, A.; Fouskovà, P.; Angelovski, G.; Balogh, E.; Mishra, A. K.; Logothetis, N.
(526 mg, 88%). 1H NMR (CDCl3) d 3.63–3.46 (signals overlapped, 5H), 3.26–3.21
(signals overlapped, 6H), 3.07 (m, 2H), 2.95–2.66 (signals overlapped, 12H)
2.41 (m, 1H), 2.25 (t, J = 7.3 Hz, 2H), 1.86 (m, 1H), 1.67–1.37 (signals
K.; Toth, E. J. Biol. Inorg. Chem. 2008, 47, 1370.
9
34. Mishra, A. K.; Chatal, J.-F. New J. Chem. 2001, 25, 336.