Synthesis and evaluation of 3-acyltetronic acid-containing metal complexing agents

Article abstract of DOI:10.1016/j.tet.2013.10.087

Potential metal chelators containing one or several acyltetronic acid moieties were prepared from cyclic or acyclic amines and polyamines, and from bis(phenols) by reaction with 1-4 equiv of 3-bromoacetyltetronic acid in the presence of potassium carbonat

Full text of DOI:10.1016/j.tet.2013.10.087

Accepted Manuscript
Synthesis and evaluation of 3-acyltetronic acid-containing metal complexing agents
Julien Rouleau, Alexandre Korovitch, Claude Lion, Miryana Hémadi, Nguyêt-Thanh
Ha-Duong, Jean Michel El Hage Chahine, Thierry Le Gall
PII:
S0040-4020(13)01648-7
10.1016/j.tet.2013.10.087
TET 24963
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 12 July 2013
Revised Date: 17 October 2013
Accepted Date: 28 October 2013
Please cite this article as: Rouleau J, Korovitch A, Lion C, Hémadi M, Ha-Duong N-T, El Hage Chahine
JM, Le Gall T, Synthesis and evaluation of 3-acyltetronic acid-containing metal complexing agents,
Tetrahedron (2013), doi: 10.1016/j.tet.2013.10.087.
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ACCEPTED MANUSCRIPT
Synthesis and evaluation of 3-acyltetronic acid-containing metal complexing agents
Julien Rouleau,a Alexandre Korovitch,b Claude Lion,b Miryana Hémadi,b Nguyêt-Thanh Ha-
Duong,b Jean Michel El Hage Chahine,b Thierry Le Galla,*
aCEA Saclay, iBiTec-S, Service de Chimie Bioorganique et de Marquage, Bât. 547, 91191
Gif-sur-Yvette, France
bUniversité Paris Diderot Sorbonne Paris Cité – CNRS, Interfaces, Traitements, Organisation
et Dynamique des Systèmes, UMR 7086, Bâtiment Lavoisier, 15 Rue Jean-Antoine de Baïf,
75205 Paris Cedex 13, France
thierry.legall@cea.fr
Abstract:
Potential metal chelators containing one or several acyltetronic acid moieties were prepared
from cyclic or acyclic amines and polyamines, and from bis(phenols) by reaction with 1-4
equivalents of 3-bromoacetyltetronic acid in the presence of potassium carbonate. The affinity
constants of the chelating agents for toxic metallic cations Cd2+, Cs+ and Pb2+ and for
dimethylarsinic acid were measured, at pH 7.5 and 9.3. Compound 4, an acyclic triamine
containing four acyltetronic moieties, was found to complex efficiently all the tested species.
Keywords:
Tetronic acid; Alkylation; Metal complexation; Affinity constant
1. Introduction
Organic compounds able to complex efficiently heavy metal cations can find application in
the sensing of these cations or for their removal from contaminated waste.1 It is thus of great
value to identify new compounds having such properties. Several natural compounds
containing a 3-acyltetronic acid moiety have been found to complex metal cations. Examples
include the ionophore tetronasin2 and the tyrosine phosphatase inhibitor RK-6823 (Figure 1).
Copper complexes of 3-acyltetronic acids have been described,4 as well as complexes of
3-alkoxycarbonyltetronic acids with salts of copper(II), cobalt(II) and zinc(II).5

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Fig. 1. Structures of 3-acyl tetronic acids
In this paper, we will describe the synthesis of a series of new chelating agents derived from
amines or polyamines, containing one or several 3-acyltetronic acid moieties.6,7 These
compounds will then be evaluated as complexing agents for selected, highly toxic species,
Pb2+, Cd2+, Cs+ and dimethylarsinic acid. Pb2+ is well known to cause health problems, such
as kidney and neurological diseases.8 Cadmium toxicity involves oxidative-stress and the
alteration of the homeostasis of essential metals such as copper and zinc. Water contamination
by arsenic is one of the biggest health threats in several countries.9 In humans and other
mammals inorganic arsenic is converted to trivalent and pentavalent methylated metabolites,
including dimethylarsinic acid. This compound has been largely employed as herbicide in
agriculture. It has been reported to induce urinary bladder tumors in rats.10 Moreover, it is
genotoxic in human cells, causing decreased DNA production and shorter DNA strands.11
Cesium is not required for biological processes and few is known about its toxicity.12 Interest
in finding agents able to complex the cesium cation stems largely from the wish to separate
radioactive cesium generated in nuclear plants.13 Such agents might also be employed for the
decorporation of radioactive cesium. Radioactive cesium was dispersed in the environment
following atmospheric nuclear explosions and also following the accidents of Chernobyl and
Fukushima. Norbadione A (Figure 2), a pigment isolated from the mushroom bay boletus
(Xerocomus badius),14 was shown to form a strong 1:1 complex with cesium chloride, owing
to two chelating moieties that both participate to the complexation.15 Likewise, we expected
that by arranging one or several 3-acyltetronic acid moieties on a template constituted by an
amine or a polyamine, would allow to obtain chelating agents able to complex the toxic
cations Pb2+, Cd2+, Cs+, as well as dimethylarsinic acid, depending on their structures.

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Fig. 2. Norbadione A
2. Results and discussion
2.1. Synthesis of 3-acyltetronic acid-containing compounds
A synthesis of bis(acyltetronic acid) derived from dodecanedioic acid was recently reported,16
according to the conditions described by Yoshii,17 using DCC, DMAP and triethylamine as
reagents. Hence, this was a potentially attracting method for the preparation of the desired
complexing agents. However, several attempts to obtain the acylation of
ethylenediaminetetraacetic acid (EDTA) with four equivalents of tetronic acid were
unsuccessful.
Another possibility to access such compounds was then envisaged, starting from amines or
polyamines and an electrophile containing already a 3-acyltetronic acid motif. For this
purpose, 3-bromoacetyltetronic acid 1 was then prepared from tetronic acid and bromoacetic
acid using the DCC/DMAP coupling (Scheme 1).
Scheme 1
Several amines or polyamines were then efficiently converted to the corresponding adducts by
reaction with 3-bromoacetyltetronic acid under mild conditions. For example, the dipodal
adduct 2 was prepared as shown in Scheme 2, by treatment of phenethylamine with 1 (two

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equivalents) in the presence of K2CO3 (two equivalents) in DMF (0°C to RT). Adduct 2 was
obtained in 66% yield after purification by reverse phase chromatography (0.01M HCO2NH4,
pH 9 / MeOH).
Scheme 2
Using a similar protocol, with varying equivalents of 1 and K2CO3, depending on the number
of possible alkylations, several adducts, tripodands 3, acyclic tetrapodands 4, 5, 6, aza-crown
ethers derivatives 7, 8, 9, were prepared from the corresponding amines and polyamines
(Table 1). Two compounds derived from bis(phenols) were also prepared similarly, using
three equivalents of bromide 1 (entries 8,9).
Table 1
Synthesis of 3-acyltetronic acids
Entry
Starting material
Equiv
product
Yield
(%)
53
1
2
1
2
3
4
4
4
4
66
37
79
5
1
96

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6
7
2
91
61
O
O
HN
NH
O
4
8
9
3
3
87
79
The preparation of the precursors of compounds 3-5 is described in the scheme 3. Amine 12,
precursor of 3, was obtained by reaction of N-Boc-phenylalanine with tetronic acid in the
presence of DCC/DMAP, followed by cleavage of the Boc (tert-butoxycarbonyl) group using
trifluoroacetic acid. The known compounds 13 and 1418 were prepared as described.
Compounds 6-11 were obtained from commercially available products.
Scheme 3

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2.2. Complexation studies
The absorption spectra of the chelators were recorded in the presence of varying
concentrations of the following species: cadmium nitrate, cesium chloride, dimethylarsinic
acid (DMA), lead(II) acetate. They were performed in two aqueous buffers, at pH = 7.5 and
9.3, except for the cadmium species which was insoluble at pH = 9.3. Compound 11 was not
evaluated, because of its low solubility in an aqueous medium. The spectra and the measured
affinity constants were similar in the two buffers, which is in agreement with the fact that the
enol functions of tetronic acids are not protonated in both neutral and basic media. In our
experiments, the lower limit of the spectrophotometric detection was of about 0.1 µM of
chelator, therefore this approach did not permit the measurements of affinities higher than 107.
The absorption spectra obtained with compound 4, upon addition of Cd2+, Cs+, Pb2+ or
dimethylarsinic acid, are indicated in Figure 3. The analysis of the data by the SPECFIT32
program showed that for all the ligands, only monocomplexes were formed.19

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Fig. 3. Variation in the absorption spectra of 4 upon addition of Cd2+ (A), Cs+ (B) and Pb2+
(D); variation of the differential absorption of 4 upon addition of Me2AsOOH, when 4 is
taken as a reference (C); spectra acquired at 25 ± 0.1 °C, pH 7.5.

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Table 2
Complexation resultsa
pH
7.5
7.5
9.3
EDTA
2
3
4
5
6
7
8
9
5.6 ± 0.3
< 2
10
Cd2+
Cs+
< 2
< 2
< 2
< 2
< 2
< 2
< 2
< 2
< 2
< 2
< 2
< 2
< 2
< 2
6.8 ± 0.2
> 7
4.0 ± 0.1
3.3 ± 0.2
4.1 ± 0.2
3.0 ± 0.3
3.1 ± 0.2
4.2 ± 0.1
4.6 ± 0.1
3.4 ± 0.1
3.9 ± 0.1
3.5 ± 0.1
4.6 ± 0.1
3.8 ± 0.1
4.3 ± 0.1
4.2 ± 0.1
3.1 ± 0.2
2.5 ± 0.3
3.6 ± 0.1
3.0 ± 0.2
2.9 ± 0.1
4.4 ± 0.1
4.1 ± 0.1
3.2 ± 0.1
4.5 ± 0.1
3.5 ± 0.2
2.6 ± 0.4
2.9 ± 0.1
4.1 ± 0.1
4.0 ± 0.1
13-14
4.3 ± 0.1 3.0 ± 0.3
4.5 ± 0.1 3.1 ± 0.3
5.4 ± 0.1 3.5 ± 0.2
5.0 ± 0.1 3.0 ± 0.1
-
< 2
-
DMA 7.5
9.3
< 2
-
< 2
-
Pb2+
7.5
5.7 ± 0.2
> 7
< 2
13-14
9.3
6.0 ± 0.2
> 7
< 2
17-18
a log of the affinity constants (log K) of compounds 2-11 and EDTA for Cd2+, Cs+, dimethylarsinic acid (DMA), and Pb2+, reported for two pH
values at 25 ± 0.1 °C.

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Affinity constants (as log K) of the synthetic chelators for three metallic cations, Cd+, Cs+ and
Pb2+ and organic dimethylarsinate are reported in the Table 2. These values are also compared
to those involving EDTA, which is considered as a universal chelator, since it forms very
strong complexes with most metals.20 EDTA seems also to form strong complexes with
inorganic As(III) and to a lesser extent with inorganic As(V).21 However, to the best of our
knowledge, EDTA does not complex Cs+ or organic arsinates.
Compounds 2 and 3 have low affinities for the four species. This may be due to the lack of
flexibility of the ligands in both chelators. Compound 9, a tetra(acyltetronic acid) derived
from cyclam (1,4,8,11-tetraazacyclotetradecane), seems to be a good chelator for Cd2+.
However, despite the fact that it is a tetrapod, it does not complex the other species. Its
affinity for Cd2+ may be related to the presence of the four nitrogen atoms and the possible
occurrence of a cage-like structure. Indeed, nitrogen is considered as a soft base and Cd2+ as a
soft acid.22 Compound 5, which is an acyclic tetra(acyltetronic acid), is a very good chelator
for Pb2+ and Cd2+, with affinities higher than 107, and can also slightly complex Cs+ and
dimethylarsinic acid. This can be due to the higher flexibility of the complexing tetronic
ligands in comparison with 9. Finally, compound 4, which differs from 5 by the presence of
two shorter spacers between nitrogen atoms, is capable of forming stable complexes with the
four tested species. As with norbadione A and its derivatives, complex formation probably
occurs by inclusion in a pseudo-cavity in which the chelating acyltetronic ligands surround
the metallic species. This cavity can be compared to that of some calixarenes, which display
similar affinities for Cs+.15d The proposed chelators are less efficient than EDTA for the
complexation of Cd2+ and Pb2+. Therefore, the most interesting chelator seems to be 4, which
has a good affinity for Cs+, and which is, to the best of our knowledge, the only organic
molecule known to form a stable complex with an organic arsinate.
3. Conclusion
We have synthesized various compounds containing one or several 3-acyltetronic acid
complexing moieties. They were obtained from a new precursor, 3-bromoacetyltetronic acid.
Affinity constants of these chelators for three metallic species, Cd2+, Cs+, Pb2+ and for
dimethylarsinic acid were measured. The best chelating agents were tetra(tetronic acids) 4 and
5 in which the tetronic acid moieties are connected to an acyclic framework. Compound 5 was
shown to efficiently complex the cesium cation as well as dimethylarsinic acid, while
compound 4 gave stable complexes with all the tested species. We envision preparing

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polymers that will incorporate such chelating agents and that will be used for the
decontamination of surfaces or water contaminated by toxic metals.
4. Experimental section
4.1. Synthesis
4.1.1. General. Dichloromethane was distilled over P2O5; commercially available anhydrous
DMF was employed. Non aqueous reactions were performed under an argon atmosphere.
TLC: Silica Gel 60F254 plates with detection by UV light and by an ethanol solution of
phosphomolybdic acid. Column chromatographies were carried out with Combiflash Serlabo
Rf75 (silica gel columns RediSep® Rf, 35-60 µm; or reversed phase columns packed with
Merck LiChroprep® RP-18, 15-25 µm). Melting points were uncorrected. NMR: 400.133 and
1
100.624 MHz for H and 13C, respectively. Chemical shifts (
δ
) are in ppm (s = singlet, d =
doublet, t = triplet, m = multiplet, b = broad), and are referenced to residual H in the
deuterated solvent as the internal standard; coupling constants (J) are in Hz.
4.1.2. 3-(2-Bromoacetyl)-4-hydroxyfuran-2(5H)-one (1). A solution of tetronic acid (4 g,
39.72 mmol, 1 equiv), triethylamine (6.625 mL, 47.67 mmol, 1.2 equiv), DMAP (465 mg,
3.9 mmol, 0.1 equiv) and bromoacetic acid (6.623 g, 47.67 mmol, 1.2 equiv) in CH2Cl2
(100 mL) was cooled to 0 °C. DCC (9.835 g, 47.67 mmol, 1.2 equiv) was added in one
portion and the mixture was stirred 30 min at 0 °C and 12 h at room temperature. The mixture
was filtered and the filtrate was recovered and then the solvents were removed under vacuum.
MeOH (300 mL) was added to the residue and the solution obtained was passed through
Dowex H+ ion exchange resin (eluent: MeOH). The solvent was removed under vacuum and
the residue was triturated with MeOH. The precipitate was filtered and dried under vacuum to
give the title compound 1 (6,172 g, 70%) as a beige powder; mp 143 °C; νmax (KBr pellet)
3191, 2993, 2970, 2942, 1753, 1661, 1460, 1349, 1224, 1106, 1046, 1014, 959, 879, 845, 759,
671 cm−1; δH (400 MHz, DMSO-d6) 4.37 (2H, s, OCH2), 4.27 (2H, s, CH2Br); δC (100 MHz,
DMSO-d6) 190.5, 183.8, 172.1, 96.6, 68.3, 35.5; HRMS (ESI−): M−H−, found 218.9303.
C6H4O4Br requires 218.9293.
4.1.3. General procedure for the alkylation of an amine by 3-bromoacetyltetronic acid. To a
solution of amine (0.45 mmol, 1 equiv) in DMF (3 mL) was added K2CO3 (188 mg,
1.36 mmol, 4 equiv). After cooling at 0 °C, a solution of 3-bromoacetyltetronic acid 1
(221 mg, 1 mmol, 2.2 equiv) in DMF (2 mL) was added dropwise. The reaction mixture was

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stirred at 0 °C for 1 h and at room temperature for 15 h. Solvent was removed under vacuum
and the residue was purified by reversed phase chromatography (aqueous 0.01 N HCO2NH4
buffer, pH9/MeOH 100/0 to 80/20) to afford the desired product.
4.1.4.
3,3'-[2,2'-(Phenethylazanediyl)bis(acetyl)]bis[4-hydroxyfuran-2(5H)-one]
(2).
Phenethylamine (57 µL, 4.53 mmol, 1 equiv), K2CO3 (188 mg, 1.36 mmol, 3 equiv) and
3-bromoacetyltetronic acid 1 (221 mg, 1 mmol, 2.2 equiv) were used following the general
procedure to afford the title compound (120 mg, 66%) as a white powder; mp 177 °C; νmax
(KBr pellet) 3445, 3194, 3030, 1732, 1651, 1463, 1353, 1262, 1146, 1044, 906, 769, 702
cm−1; δH (400 MHz, CD3OD) 7.24 (5H, m, H−Ar), 4.52 (4H, s, CH2O), 4.27 (4H, s, CH2CO),
3.50 (2H, m, CH2CH2N), 3.04 (2H, m, CH2CH2N); δC (100 MHz, CD3OD) 195.7 (2C),
182.0 (2C), 176.1 (2C), 136.0, 128.4 (2C), 128.5 (2C), 126.7, 94.4 (2C), 70.3 (2C), 61.3 (2C),
57.2, 30.4; HRMS (ESI−): M−H−, found 400.1032. C20H18NO8 requires 400.1032.
4.1.5.
3,3'-(2,2'-{[1-(4-Hydroxy-2-oxo-2,5-dihydrofuran-3-yl)-1-oxo-3-phenylpropan-2-
yl]azanediyl}bis[acetyl])bis[4-hydroxyfuran-2(5H)-one] (3). Amine 12 (97 mg, 0.39 mmol,
1 equiv), K2CO3 (119 mg, 0.86 mmol, 2.2 equiv), 3-bromoacetyltetronic acid 1 (191 mg,
0.86 mmol, 2.2 equiv) and DMF (2 mL) were used following the general procedure to afford
the title compound (109 mg, 53%) as a white powder; mp 197 °C; νmax (KBr pellet) 3449,
3186, 1731, 1651, 1463, 1357, 1262, 1146, 1045, 905, 771, 704 cm−1; δH (400 MHz, D2O)
7.71 (5H, m, H−Ar), 5.53 (1H, dd, J = 8.8, 5.9 Hz, CHBn), 4.52 (1H, d, J = 17.8 Hz, CHHO),
4.45 (1H, d, J = 17.8 Hz, CHHO), 4.26 (2H, s, CH2O), 4.21 (2H, s, CH2O), 4.17 (3H, m,
CH2N), 4.02 (1H, d, J = 17.6 Hz, CH2N), 3.09 (1H, dd, J = 14.8, 5.9 Hz, CHHPh), 2.93 (1H,
dd, J = 14.8, 8.8 Hz, CHHPh); δC (100 MHz, D2O) 197.1, 197.0, 196.8, 187.0, 182.9, 182.8,
176.9 (2C), 176.6, 134.1, 129.0 (2C), 128.7 (2C), 127.4, 96.2, 95.1 (2C), 70.7, 70.6, 70.5,
68.2, 61.1, 59.3, 34.5; HRMS (ESI): MH+, found 528.1133. C25H22NO12 requires 528.1142.
4.1.6.
3,3',3'',3'''-(2,2',2'',2'''-{[(Phenethylazanediyl)bis(ethane-2,1-
diyl)]bis(azanetriyl)}tetrakis[acetyl])tetrakis[4-hydroxyfuran-2(5H)-one] (4). Triamine 13
(146 mg, 0.70 mmol, 1 equiv), K2CO3 (437 mg, 3.17 mmol, 4.5 equiv), 3-bromoacetyltetronic
acid 1 (655 mg, 2.96 mmol, 4.2 equiv) and DMF (10 mL) were used following the general
procedure to afford the title compound (359 mg, 66%) as a light pink powder; mp 195 °C
(decomposition); νmax (KBr pellet) 3448, 3191, 1729, 1648, 1464, 1261, 1045, 913, 770, 703

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cm−1; δH (400 MHz, D2O) 7.22 (4H, m, H−Ar), 7.15 (1H, m, H−Ar), 4.38 (8H, s, CH2O), 4.32
(8H, s, CH2CO), 3.35 (4H, m, NCH2), 2.98 (4H, m, NCH2), 2.85 (2H, m, CH2Bn), 2.75 (2H,
m, CH2Ph); δC (100 MHz, D2O) 196.9 (4C), 183.0 (4C), 176.7 (4C), 139.5, 128.6 (2C), 128.5
(2C), 126.3, 95.2 (4C), 70.7 (4C), 61.1 (4C), 54.2, 53.0 (2C), 47.9 (2C), 31.7; HRMS (ESI):
MH+, found 768.2252. C36H38N3O16 requires 768.2289.
4.1.7.
3,3',3'',3'''-(2,2',2'',2'''-{[(Phenethylazanediyl)bis(propane-3,1-
diyl)]bis(azanetriyl)}tetrakis[acetyl])tetrakis[4-hydroxyfuran-2(5H)-one] (5).
Triamine 14 (35 mg, 0.15 mmol, 1 equiv), K2CO3 (82 mg, 0.595 mmol, 4 equiv), 3-
bromoacetyltetronic acid 1 (132 mg, 0.595 mmol, 4 equiv) and DMF (2 mL) were used
following the general procedure to afford the title compound (44 mg, 37%) as a light pink
powder; mp 220 °C (decomposition); νmax (KBr pellet) 3442, 1729, 1648, 1464, 1357, 1262,
916, 769, 702 cm−1; δH (400 MHz, D2O) 7.40-7.20 (5H, m, H−Ar), 4.36 (16H, s, CH2O,
CH2CO), 3.38 (6H, m), 3.26 (4H, m), 2.97 (2H, m), 2.13 (4H, m, CH2CH2CH2); δC (100
MHz, D2O) 196.8 (4C), 189.4 (4C), 177.4 (4C), 137.4, 128.7 (2C) 128.5 (2C), 126.8, 95.8
(4C), 70.4 (4C), 61.3 (4C), 60.9 (2C), 53.7, 51.6 (2C), 28.7, 19.9 (2C); HRMS (ESI): MH+,
found 796.2555. C38H42N3O16 requires 796.2565.
4.1.8.
1,14-Bis(4-hydroxy-2-oxo-2,5-dihydrofuran-3-yl)-3,12-bis[2-(4-hydroxy-2-oxo-2,5-
dihydrofuran-3-yl)-2-oxoethyl]-6,9-dioxa-3,12-diazatetradecane-1,14-dione (6). 2,2'-[Ethane-
1,2-diylbis(oxy)]diethanamine (45 µL, 0.31 mmol, 1 equiv), K2CO3 (187 mg, 1.35 mmol,
4.4 equiv), 3-bromoacetyltetronic acid 1 (300 mg, 1.35 mmol, 4.4 equiv) and DMF (2 mL)
were used following the general procedure to afford the title compound (173 mg, 79%) as a
light pink powder; mp 255 °C (decomposition); νmax (KBr pellet) 3449, 2933, 1725, 1648,
1449, 1362, 1248, 1089, 1059, 918, 832, 771, 705 cm−1; δH (400 MHz, D2O) 4.26 (8H, s,
CH2O), 4.01 (8H, s, CH2CO), 3.57 (4H, m, OCH2CH2N), 3.45 (4H, s, OCH2CH2O), 2.97 (4H,
m, OCH2CH2N); δC (100 MHz, D2O) 196.8 (4C), 177.8 (C4), 160.9 (4C), 96.0 (4C), 70.4
(4C), 69.4 (4C), 67.3 (2C), 61.7 (2C), 54.4 (2C); HRMS (ESI): MH+, found 709.1729.
C30H33N2O18 requires 709.1728.
4.1.9.
3-[2-(1,4,7,10,13-Pentaoxa-16-azacyclooctadecan-16-yl)acetyl]-4-hydroxyfuran-
2(5H)-one (7). 1,4,7,10,13-Pentaoxa-16-azacyclooctadecane (108 mg, 0.41 mmol, 1 equiv),

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K2CO3 (62 mg, 0.45 mmol, 1.1 equiv), 3-bromoacetyltetronic acid 1 (100 mg, 0.45 mmol,
1.1 equiv) and DMF (2 mL) were used following the general procedure to afford the title
compound (158 mg, 96%) as a white powder; mp 130-132 °C; νmax (KBr pellet) 3495, 2895,
1718, 1654, 1584, 1436, 1352, 1248, 1106, 958, 836, 767, 698 cm−1; δH (400 MHz, D2O) 4.37
(2H, s, CH2O), 4.15 (2H, s, CH2CO), 3.67 (16H, s, OCH2CH2O), 3.63 (4H, s, NCH2CH2O),
3.22 (4H, s, NCH2CH2O); δC (100 MHz, D2O) 197.1, 184.6, 177.3, 95.5, 70.7, 69.7 (2C), 69.6
(2C), 69.4 (2C), 69.3 (2C), 64.2 (2C), 55.6, 55.4 (2C); HRMS (ESI): MNa+, found 426.1750.
C18H29NO9Na requires 426.1740.
4.1.10.
3,3'-[2,2'-(1,4,10-Trioxa-7,13-diazacyclopentadecane-7,13-diyl)bis(acetyl)]bis[4-
(8). 1,4,10-Trioxa-7,13-diazacyclopentadecane (100 mg,
hydroxyfuran-2(5H)-one]
0.46 mmol, 1 equiv), K2CO3 (133 mg, 0.96 mmol, 2.1 equiv), 3-bromoacetyltetronic acid 1
(213 mg, 0.96 mmol, 2.1 equiv) and DMF (3 mL) were used following the general procedure
to afford the title compound (208 mg, 91%) as a white powder; mp 230 °C (decomposition);
νmax (KBr pellet) 3440, 3235, 2875, 1717, 1633, 1463, 1354, 1251, 1115, 1096, 1045, 938,
774, 704 cm−1; δH (400 MHz, D2O) 4.37 (4H, s, CH2O), 4.09 (4H, s, CH2CO), 3.73 (4H, t, J =
4.6 Hz), 3.70 (4H, s, OCH2CH2O), 3.67 (4H, t, J = 4.8 Hz), 3.12 (8H, bs, NCH2CH2O); δC
(100 MHz, D2O) 197.3 (2C), 183.3 (2C), 177.0 (2C), 95.3 (2C), 70.9 (2C), 69.9 (2C), 63.6
(2C), 63.5 (2C), 60.3 (2C), 55.6 (2C), 54.0 (2C); HRMS (ESI): MNa+, found 521.1764.
C22H30N2O11Na requires 521.1747.
4.1.11.
3,3',3'',3'''-[2,2',2'',2'''-(1,4,8,11-Tetraazacyclotetradecane-1,4,8,11-
(9). 1,4,8,11-
tetrayl)tetrakis(acetyl)]tetrakis[4-hydroxyfuran-2(5H)-one]
Tetraazacyclotetradecane (22 mg, 0.11 mmol, 1 equiv), K2CO3 (62 mg, 0.45 mmol,
4.1 equiv), 3-bromoacetyltetronic acid 1 (100 mg, 0.45 mmol, 4.1 equiv) and DMF (2 mL)
were used following the general procedure to afford the title compound (51 mg, 61%) as a
white powder; mp 225-230 °C (decomposition); νmax (KBr pellet) 3444, 2848, 1731, 1644,
1471, 1362, 1253, 1046, 923, 770, 705 cm−1; δH (400 MHz, D2O) 4.19 (8H, br s, CH2O), 3.94
(8H, br s, CH2CO), 3.60-2.70 (16H, m, NCH2CH2N,NCH2CH2CH2N), 1.83 (4H, m,
NCH2CH2CH2N); δC (100 MHz, D2O) 196.8 (4C), 193.3 (4C), 178.2 (4C), 96.6 (4C), 70.3
(4C), 61.0 (4C), 50.9 (4C), 47.2 (4C), 20.1 (2C); HRMS (ESI): MH+, found 761.2529.
C34H41N4O16 requires 761.2518.

ACCEPTED MANUSCRIPT
4.1.12.
3,3'-(2,2'-{[1,1'-Biphenyl]-2,2'-diylbis(oxy)}bis[acetyl]}bis[4-hydroxyfuran-2(5H)-
one] (10). 2,2’-Biphenol (19 mg, 0.102 mmol, 1 equiv), K2CO3 (31mg, 0.226 mmol,
2.2 equiv), 3-bromoacetyltetronic acid 1 (50 mg, 0.226 mmol, 2.2 equiv) and DMF (1 mL)
were used following the general procedure to afford the title compound (42mg, 87%) as a
white powder; mp 178-180 °C; νmax (KBr pellet) 3247, 3050, 1720, 1606, 1458, 1410, 1370,
1237, 1147, 1121, 1050, 931, 859, 758, 707 cm−1; δH (400 MHz, CD3OD) 7.30-7.20 (4H, m,
H−Ar), 6.99 (2H, t, J = 7.6 Hz, H−Ar), 6.87 (2H, d, J = 8.4 Hz, H−Ar), 5.07 (4H, s, CH2OAr),
4.28 (4H, s, CH2OCO); δC (100 MHz, DMSO-d6) 193.4 (2C), 186.9 (2C), 174.6 (2C), 155.9
(2C), 131.9 (2C), 128.0 (2C), 126.7 (2C), 119.5 (2C), 112.3 (2C), 93.8 (2C), 71.1 (2C), 69.5
(2C); HRMS (ESI): MNa+, found 489.0802. C24H18NaO10 requires 489.0798.
4.1.13. 3,3'-{2,2'-[Naphthalene-1,7-diylbis(oxy)]bis(acetyl)}bis[4-hydroxyfuran-2(5H)-one]
(11). 1,7-naphthalenediol (241 mg, 1.5 mmol, 1 equiv), K2CO3 (1.245 g, 9.0 mmol, 6 equiv),
3-bromoacetyltetronic acid 1 (1.0 g, 4.51 mmol, 3 equiv) and DMF (10 mL) were used
following the general procedure to afford the title compound (524 mg, 79%) as a white
powder; mp 238-240 °C; νmax (KBr pellet) 3181, 1729, 1629, 1512, 1466, 1364, 1247, 1220,
1046, 939, 826, 779, 742, 693, 638 cm−1; δH (400 MHz, DMSO-d6) 7.75 (1H, d, J = 9.2 Hz,
H−Ar), 7.43 (1H, d, J = 2.4 Hz, H−Ar), 7.34 (1H, d, J = 8.0 Hz, H−Ar), 7.10-7.25 (4H, m,
H−Ar, OH), 6.58 (1H, d, J = 7.6 Hz, H−Ar), 5.20 (2H, s, CH2OAr), 5.11 (2H, s, CH2OAr),
4.16 (2H, s, CH2OCO), 4.15 (2H, s, CH2OCO); δC (100 MHz, DMSO-d6) 193.6 (2C), 186.4,
186.0, 174.7, 174.6, 156.2, 153.2, 129.3, 128.9, 125.9, 123.4, 119.4, 118.8, 105.6, 101.5, 93.9,
93.8, 70.9 (2C), 69.63, 69.58; HRMS (ESI): MNa+, found 463.0636. C22H16NaO10 requires
463.0641.
4.1.14. 3-(2-Amino-3-phenylpropanoyl)-4-hydroxyfuran-2(5H)-one (12). To a solution of
tetronic acid (94 mg, 0.94 mmol, 1 equiv) in CH2Cl2 cooled at 0 °C were added triethylamine
(157 µL, 1.13 mmol, 1.2 equiv), DMAP (11 mg, 0.094 mmol, 0.1 equiv), N-Boc-
phenylalanine (299 mg, 1.13 mmol, 1.2 equiv) and DCC (232 mg, 1.13 mmol, 1.2 equiv). The
mixture was stirred for 30 min at 0 °C and for 15 h at room temperature. The mixture was
filtered and the solvent was removed under vacuum. Then, CH2Cl2 (2 mL) and trifluoroacetic
acid (2 mL) were added to the residue and the mixture was stirred at room temperature for 1.5
h. After concentration under vacuum, the obtained residue was purified by reversed phase
chromatography (aqueous 0.01 N HCO2NH4 buffer, pH9/MeOH 100/0 to 90/10) to afford the

ACCEPTED MANUSCRIPT
title compound (161 mg, 70%) as a white powder; mp 225-230 °C (decomposition); νmax
(KBr pellet) 3030, 1715, 1645, 1363, 1247, 1140, 1048, 1030, 963, 917, 787, 746, 699 cm−1;
δH (400 MHz, CD3OD) 7.40 (2H, d, J = 7.0 Hz, H−Ar), 7.30 (2H, m, H−Ar), 7.24 (1H, m,
H−Ar), 4.99 (1H, dd, J = 9.7, 3.7 Hz, CHCO), 4.31 (2H, s, CH2O), 3.29 (1H, dd, J = 14.3 Hz,
3.7 Hz, CHHPh), 2.78 (1H, dd, J = 14.3 Hz, 9.7 Hz, CHHPh); δC (100 MHz, CD3OD) 195.6,
187.0, 176.6, 135.5, 129.2 (2C), 128.6 (2C), 127.1, 93.8, 70.3, 65.6, 57.4, 36.9; HRMS (ESI):
MNa+, found 270.0738. C13H13NO4Na requires 270.0742.
4.2. Complexation studies
Absorption measurements were performed at 25 ± 0.1 °C on a Cary 4000 spectrophotometer
equipped with Peltier thermostated cell-carriers. The pH of solutions was measured at 25 ±
0.5 °C with a Jenco pH-meter. Affinity constants were determined spectrophotometrically by
the use of the Global Analysis program SPECFIT32. SPECFIT32 is a multivariate data
analysis program for data sets that are obtained from multiwavelength spectrophotometric
measurements. The program utilizes a specially adapted version of the Levenberg-Marquardt
method. This procedure returns optimized model parameters, their standard errors, and the
predicted spectra of the unknown colored species.19 The affinity constants were checked when
possible by a variant of the Benesi and Hildebrand method.
Acknowledgments
Financial support by the Agence Nationale de la Recherche (ANR-08-SECU-002) is
gratefully acknowledged.
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ACCEPTED MANUSCRIPT
Synthesis and evaluation of new 3-acyltetronic acid-containing metal complexing agents
Julien Rouleau, Alexandre Korovitch, Claude Lion, Miryana Hémadi, Nguyêt-Thanh Ha-Duong, Jean
Michel El Hage Chahine, and Thierry Le Gall.
Graphical abstract :

ACCEPTED MANUSCRIPT
Synthesis and evaluation of new 3-acyltetronic acid-containing metal complexing agents
Julien Rouleau,a Alexandre Korovitch,b Claude Lion,b Miryana Hémadi,b Nguyêt-Thanh Ha-
Duong,b Jean Michel El Hage Chahine,b Thierry Le Galla,*
aCEA Saclay, iBiTec-S, Service de Chimie Bioorganique et de Marquage, Bât. 547, 91191 Gif-sur-
Yvette, France
bUniversité Paris Diderot Sorbonne Paris Cité – CNRS, Interfaces, Traitements, Organisation et
Dynamique des Systèmes, UMR 7086, Bâtiment Lavoisier, 15 Rue Jean-Antoine de Baïf, 75205
Paris Cedex 13, France
Supporting information
Contents:
Copies of 1H NMR and 13C NMR spectra of compounds 1-12
S2-S13
S-1

ACCEPTED MANUSCRIPT
1H and 13C NMR spectra of compound 1 (DMSO-d6)
tlgj103b 1H
Current Data Parameters
NAME
EXPNO
PROCNO
tlgj103b
10
1
F2 - Acquisition Parameters
Date_
Time
INSTRUM
PROBHD
PULPROG
TD
20120921
11.08
spect
5 mm PABBO BB-
zg45
65536
DMSO
8
SOLVENT
NS
DS
SWH
0
5995.204 Hz
FIDRES
AQ
0.091480 Hz
5.4657526 sec
228.1
RG
DW
83.400 usec
6.00 usec
DE
TE
297.6 K
D1
1.00000000 sec
0.00000000 sec
0.01500000 sec
MCREST
MCWRK
======== CHANNEL f1 ========
NUC1
P1
PL1
SFO1
1H
7.00 usec
-4.00 dB
400.1324000 MHz
F2 - Processing parameters
SI
65536
SF
400.1300079 MHz
WDW
SSB
LB
GB
PC
EM
0
1.00 Hz
0
1.00
9
8
7
6
5
4
3
2
1
ppm
TLG J-103
220
200
180
160
140
120
100
80
60
40
20
ppm
S-2

ACCEPTED MANUSCRIPT
1H and 13C NMR spectra of compound 2 (CD3OD)
O
HO
O
O
N
O
OH
O
O
S-3

ACCEPTED MANUSCRIPT
1H and 13C NMR spectra of compound 3 (D2O)
O
O
HO
O
O
O
O
O
N
O
O
Ph
OH
HO
S-4

ACCEPTED MANUSCRIPT
1H and 13C NMR spectra of compound 4 (D2O)
O
O
N
OH
Ph
O
O
O
N
O
O
O
O
O
HO
N
O
O
OH
HO
S-5

ACCEPTED MANUSCRIPT
S-6

ACCEPTED MANUSCRIPT
1H and 13C NMR spectra of compound 5 (D2O)
1400
1300
1200
1100
1000
900
800
700
600
500
400
300
200
100
0
163C
O
O
OH
O
O
O
HO
O
N
N
HO
O
O
O
N
Ph
OH
O
O
O
8.0
7.5
7.0
6.5
6.0
5.5
5.0
4.5
4.0
f1 (ppm)
3.5
3.0
2.5
2.0
1.5
1.0
0.5
0.0
S-7

ACCEPTED MANUSCRIPT
1H and 13C NMR spectra of compound 6 (D2O)
4500
4000
3500
3000
2500
2000
1500
1000
500
O
O
O
HO
O
O
N
HO
O
O
N
O
O
OH
O
HO
O
O
O
O
0
8.0
7.5
7.0
6.5
6.0
5.5
5.0
4.5
4.0
f1 (ppm)
3.5
3.0
2.5
2.0
1.5
1.0
0.5
0.0
DMF
DMF
S-8

ACCEPTED MANUSCRIPT
1H and 13C NMR spectra of compound 7 (D2O)
O
O
O
O
O
O
O
O
N
HO
S-9

ACCEPTED MANUSCRIPT
1H and 13C NMR spectra of compound 8 (D2O)
O
O
O
O
O
N
N
HO
O
O
HO
O
O
13000
12000
11000
10000
9000
8000
7000
6000
5000
4000
3000
2000
1000
0
TLG 186B
-1000
200
190
180
170
160
150
140
130
120
110
100
f1 (ppm)
90
80
70
60
50
40
30
20
10
0
S-10