Sequestering agent for uranyl chelation: New binaphtyl ligands

Article abstract of DOI:10.1016/j.tetlet.2011.05.075

The synthesis of phosphonate, sulfocatecholamide (CAMS) and hydroxypyridinone (HOPO) binaphtyl ligands is presented. Their binding abilities for uranyl cation were determined by UV spectrophotometry in aqueous media versus pH. These titrations showed that

Full text of DOI:10.1016/j.tetlet.2011.05.075

Tetrahedron Letters 52 (2011) 3973–3977
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Tetrahedron Letters
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Sequestering agent for uranyl chelation: new binaphtyl ligands
Antoine Leydier a, Delphine Lecerclé b, Stéphane Pellet-Rostaing a, , Alain Favre-Reguillon a, Frédéric Taran b,
⇑
Marc Lemaire a
a ICBMS, Institut de Chimie et Biochimie Moléculaires et Supramoléculaires, CNRS, UMR 5246, Université de Lyon, INSA, CPE, Laboratoire de Catalyse et Synthèse Organique,
43 Bd du 11 novembre 1918, Villeurbanne F-69622, France
b Service de Chimie Bio-organique et de Marquage, iBiTec-S, CEA-Saclay, 91191 Gif sur Yvette, France
a r t i c l e i n f o
a b s t r a c t
Article history:
The synthesis of phosphonate, sulfocatecholamide (CAMS) and hydroxypyridinone (HOPO) binaphtyl
ligands is presented. Their binding abilities for uranyl cation were determined by UV spectrophotometry
in aqueous media versus pH. These titrations showed that the efficiency of these chelating agents
depends on the nature of the chelating group. Each ligand shows a more or less pronounced affinity
towards uranium. While the bisphosphonate compound did not show any affinity towards the uranyl
ion, the BINHOPO derivative exhibits significant affinity at acidic and neutral pH while the BINCAMS is
more efficient at basic pH.
Received 20 November 2010
Revised 15 May 2011
Accepted 16 May 2011
Available online 23 May 2011
Keywords:
CAMS
Dipodal ligands
Binol
Ó 2011 Elsevier Ltd. All rights reserved.
Chelates
Actinides
Uranium
1. Introduction
decorporation efficacy of poly-phosphonated compounds,7 particu-
larly concerning ethane-1-hydroxy-1,1-bisphosphonate EHBP.8–11
Commonly used as nuclear fuel in fission reactors for civilian
purpose, uranium can be introduced into the human body in the
case of internal contamination by ingestion, inhalation or through
wounds. The hexavalent uranyl ion (UO22þ, U(VI)) was proven to
be the most stable form in vivo1 and is complexed in the blood by
chelating agents such as proteins or carbonates. Distribution of
toxic species and retention in target organs, such as kidneys, liver
or marrow occur2 after chelation, potentially inducing chemical
intoxication, especially in the case of heavy metal contamination.3
To avoid these effects, heavy metals must be eliminated from the
body by administering nontoxic chelating agents able to form sta-
ble complex with uranyl ions so that the body can rapidly excrete
the poison from blood and target organs. Thus toxic material con-
centrations and radiation doses, and subsequently tumour risks
may be reduced. Until now, only a few ligands that are able to
strongly bind U(VI) in vivo, promote its excretion and efficiently
prevent or reduce deposition in kidneys and bones, the two main
target organs of U(VI). Since the 1980’s, several effective uranyl
ligands were synthesised, based on different complexing functions.
Phosphorus containing molecules, especially bisphosphonates,
were found to be very effective uranyl ligands.4–6 Few significant
decorporation works have been reported so far concerning the
Decorporation with bidentate methylterphthalimide (MeTAM)-
based chelating ligands was also studied and appeared not to be
suitable for biological decorporation due to their high toxicity.12
Sulfocatechol Tiron proved to be effective for U(VI) complexation
in vivo within the physiological pH range,13,14 but a modest suc-
cessful reduction of acute U(VI) toxicity and reduction of body
U(VI) with this ligand was observed. Therefore, multidentate ana-
logues containing sulfocatecholamide (CAMS) or structurally anal-
ogous hydroxyl-pyridone (HOPO) units would be effective for
in vivo chelation of U(VI).15,16 Indeed, pioneering work performed
by Raymond and co-workers on uranyl-sequestering agents based
on 3-hydroxy-2(1H)-pyridinone (3,2-HOPO)17 and sulfocatechola-
mide (CAMS) ligands resulted in two low-toxicity ligands 5-LI-
CAM(S) and 5-LIO(Me-3,2-HOPO),16 both efficient chelating
agents of circulating U(VI) in the body. Recently, we described the
synthesis and the evaluation of several 5-CAMS analogues incorpo-
rating various diamine skeletons such as the 5-CYCAMS (Fig. 1).18
We also described several calixarene based compounds functional-
ized with (1,2)HOPO or CAMS chelating units.19 In both case, the
chelating properties towards uranium were studied in aqueous
media by UV–Vis analysis and NMR spectroscopy and some of these
showed pronounced affinity for the target ion. Since 1990, the
enantiomeric atropoisomers of 1,10-binaphthyl-2,20-diol (Binol)
have become among the most widely used ligands for both stoichi-
ometric and catalytic asymmetric reactions.20 2,20-Binaphthol
⇑
Corresponding author.
E-mail address: antoine.leydier@cpe.fr (S. Pellet-Rostaing).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.05.075

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A. Leydier et al. / Tetrahedron Letters 52 (2011) 3973–3977
SO3H
HO3S SO3H
HO3S
H
H
O
N
N
O
O
O
OH
OH
OH
OH
HO
HO
HN
OH HO
O
O
NH
HO S
3
SO H
3
5-CYCAMS
HO
SO3H
HO3S
OH
1,3-calix-CAMS
Figure 1. Uranyl 5-CAMS and 1,3-calix-CAMS.
(Binol) and its derivatives have generated particular interest be-
cause their versatile backbone can be modified, thereby affecting
the reaction environment by influencing the properties of the metal
centre. Substitution of Binol may affect not only the steric environ-
ment around the metal centre but also the electronic properties of
the oxygen atoms, which are common constituents of the Lewis
acidic–metal complexes.21
Recently, Yu reported a family of Binol derivatives exhibiting a
good ability to complex lanthanides.22,23 During the same period,
new macrocyclic structures including Binol and salen units were
studied and their uranium complexes isolated.24,25 As far as we
know, combination of the Binol structure with the chelating behav-
iour of sulfocatechol amides has not been reported in the literature
as well as the phosphonate and HOPO derivatives. We present here
the synthesis and the chelating properties of new racemic Binol
derivatives containing phosphonate, HOPO or CAMS functions.
using HCl in acetic acid for the HOPO pendant arms to give the
BINHOPO 11 in 98% yields. Hydrogenolysis of catechol 7 led to 8
in 98% yield.
Sulfonation of 8 in hot sulfuric acid followed by precipitation in
diethyl ether gave the desired pure BINCAMS 9 in good yield. In
parallel, sulfonation of BINHOPO 11 failed, leading to a complex
mixture of partially polysulfonated compounds. Each component
was fully characterised by 1H NMR, 13C NMR and mass
spectroscopy.
The complexation behaviour of compounds 3, 9 and 11 towards
the uranyl cation was studied by the spectrophotometric method
developed by Taran and co-workers,4 based on a competitive ura-
nium binding by using sulfochlorophenol SCP as a chromogenic
chelate, assuming that 1:1 metal/ligand complexes are formed as
it was also demonstrated through NMR studies in earlier
works.18,19 This latter was found highly suitable for a rapid screen-
ing of putative library of uranium ligand and compared with 5-LIC-
AMS, synthesised as previously described by Raymond and co-
workers (Table 1).12 Globally, the bisphosphonate Binol 3 does
not give satisfactory results while the Binol CAMS 9 gives slightly
better results than the reference 5-LICAMS at pH 5.5. The HOPO Bi-
nol 11 exhibits high Kcond enhancement under basic conditions in
accordance with previous findings.18,19 At pH 7.4, none of the syn-
thesised Binol displaced SCP/uranyl complexation equilibrium bet-
ter than the 5-LICAMS. At pH 9, 11 exhibited a larger complexation
2. Results and discussion
The dibromo Binol 1 was obtained as described in the litera-
ture.26 Heating 1 in triethylphosphite gave the bisdiethylphosphite
Binol 2. Deprotection of 2 was achieved by using trimethylsilyl
bromide27 without further purification to give 3 in 59% overall
yield (Fig. 2). Acid chloride derivatives 4 and 5 were obtained by
the reaction of oxalyl chloride with O-benzyl catechol28,29 and N-
benzyl HOPO30–32 carboxylic acids preliminary synthesised follow-
ing the previously described procedures16 in dichloromoethane
with a catalytic amount of DMF in quantitative yield. Bis-amide
analogues 7 and 10 were obtained by condensation of the corre-
sponding acid chloride derivatives 4 and 5 with the diamino-Binol
6 prepared according to a described procedure33 in the presence of
Et3N (Fig. 3). Deprotection of the hydroxyl groups was achieved
efficiency (log Kcond = 21) towards UO2þ. Except with the 1,3-
2
calixCAMS,19 such a very large stability constant has never been
observed with CAMS ligands.
3. Experimental part
All the organic reagents used were pure commercial products
from Aldrich, Acros, Fluka, Avocado, Lancaster & Maybridge. The
solvents were purchased from Carlo Erba, Acros, Pro-Labo, Fluka
& Aldrich. Anhydrous solvents came from Acros, anhydrous THF
and dry CH2Cl2 were distilled. Flash chromatography was carried
out on Merck Silica Si60 (40–63 mm). 1H, 13C NMR spectra were re-
corded on a Bruker AC-200 (200.13 MHz for 1H, 50.32 MHz for 13C)
or AC-300 FT (300.13 MHz for 1H, 75.46 MHz for 13C) spectrome-
ter; d values are given in parts per million and J in hertz. Elemental
analyses (C, H, N, S, O, F) were obtained from the Service Central
d’Analyse of the CNRS (Solaize). High resolution mass spectra: HR
LSIMS (Liquid Secondary Ionisation Mass Spectrometry: Thioglyc-
erol), HR CIMS (Isobutan) and HR EIMS were carried out on a Finn-
eganMAT 95xL by the UCBL Centre de Spectroscopie de Masse.
Compound 3: To a magnetically stirred solution of Binol
(1.303 g, 4.55 mmol) and triphenylphosphine (3.58 g, 13.6 mmol)
in 40 mL dry THF at ambient temperature under N2 atmosphere
was added dropwise a mixture of 2-bromoethanol (0.97 mL,
Br
PO(OEt)2
O
O
P(OEt)3
O
O
Br
PO(OEt)2
2
1
TMSBr
PO(OH)2
O
O
PO(OH)2
Global Yield =
59%
3
Figure 2. Access to bisphosphonate Binol compound.

A. Leydier et al. / Tetrahedron Letters 52 (2011) 3973–3977
3975
O
Cl
N
5
O
O
OBn
N
O
O
NH2
NH2
NH OR
NEt3, CH2Cl2
O
O
O
O
O
(58%)
NH OR
N
6
R = Bn
R = H
10
11
AcOH
O
Cl
HCl/H2O
NEt3, CH2Cl2
(48%)
( 98%)
OBn
OBn
SO3H
4
O
O
O
OR
HO3S
OH
NH OR
NH OH
NH OH
O
O
O
O
1) H2SO4, 50°C, 24h
2) Et2O
(75%)
NH OR
OR
HO3S
OH
O
R = Bn
R = H
7
8
H2
THF
Pd/C
9
(98%)
SO3H
Figure 3. Acces to BINHOPO and BINCAMS.
Table 1
1.13 (m, 12H, P–O–CH2–CH3). 13C NMR (CDCl3, 75 MHz, 25 °C) d
(ppm): 154.0 (Ar–C), 134.5 (Ar–C), 129.9 (Ar–CH), 128.3 (Ar–CH),
126.8 (Ar–CH), 125.8 (Ar–CH), 124.3 (Ar–CH), 121.1 (Ar–C), 116.2
(Ar–CH), 64.0–64.5 (d, CH2–CH2–P), 62.0 (CH2–CH3), 27.9–26.1 (d,
CH2–P), 16.6 (CH3). HRMS (ESI): calcd for C32H40P2O8Na+:
637.2091; found: 637.2089.
Kcond of ligand-UO2þ at several pH values ( 0.1)
2
pH
Log Kcond U-L/(pH)
5.5
7.4
9.0
5-LICAMS
3
9
11
11.1
<8
11.3
10.0
17.0
<13
15.8
16.2
19.4
<15
17.8
21
To 700 mg of 2 mixed with P(OEt)3 (70% purity) (1.4 mmol) in
15 mL dry acetonitrile were added 2.4 mL of TMSBr (13 equiv).
The mixture was refluxed for 24 h. After cooling, 15 mL of metha-
nol was added and the mixture heated at 65 °C for 2 h, evaporated,
30 mL water was added. The resulting precipitate was dissolved in
methanol. Precipitation with acetone/diethyl ether (20 mL/20 mL)
and filtration afforded pure 3 as a grey powder (415 mg, 59%). 1H
NMR (DMSO-d6, 300 MHz, 25 °C) d (ppm): 8.04 (d, J = 9.0 Hz, 2H,
Ar–H), 7.93 (d, J = 8.1 Hz, 2H, Ar–H), 7.56 (d, J = 9.0 Hz, 2H, Ar–H),
7.34 (t, J = 7.2 Hz, 2H, Ar–H), 7.22 (t, J = 7.2 Hz, 2H, Ar–H), 6.91 (d,
J = 8.1 Hz, 2H, Ar–H), 6.62 (br s, 4H, PO(OH)2), 4.19 (m, 4H, O–
CH2–CH2–P), 1.76 (m, 4H, O–CH2–CH2–P).13C NMR (DMSO-d6,
75 MHz, 25 °C) d (ppm): 153.8 (Ar–C), 133.8 (Ar–C), 129.9 (Ar–
CH), 129.3 (Ar–C), 128.4 (Ar–CH), 127.0 (Ar–CH), 125.0 (Ar–CH),
124.0 (Ar–CH), 120.1 (Ar–C), 116.2 (Ar–CH), 64.8 (CH2–CH2–P),
39.8–40.6 (m, CH2–P).
13.6 mmol) and azodicarboxylic acid diethyl ester (DEAD, 2.15 mL,
13.6 mmol). The reaction mixture was then slowly warmed to re-
flux. After being refluxed for 7 h the mixture was cooled to ambient
temperature and the solvents were removed under reduced pres-
sure to give a pale yellow oil. The crude product was chromato-
graphed on a silica gel column (CH2Cl2/cyclohexane, 1:3) to give
1 (1.47 g; 63%) as colourless needles. 1H NMR (CDCl3, 300 MHz,
25 °C) d (ppm): 7.97 (d, J = 8.4 Hz, 2H, Ar–H), 7.88 (d, J = 8.4 Hz,
2H, Ar–H), 7.21–7.31 (m, 4H, Ar–H), 7.10–7.15 (m, 2H, Ar–H),
7.04 (d, J = 8.5 Hz, 2H, Ar–H), 4.17–4.12 (m, 4H, O–CH2–CH2–Br),
3.10 (t, J = 6.7 Hz, 4H, O–CH2–CH2–Br). 13C NMR (CDCl3, 75 MHz,
25 °C) d (ppm): 154.0 (Ar–C), 134.5 (Ar–C), 130.2 (Ar–CH), 128.5
(Ar–CH), 127.0 (Ar–CH), 125.9 (Ar–CH), 124.6 (Ar–CH), 121.5
(Ar–C), 116.8 (Ar–CH), 70.4 (CH2), 29.7 (CH2). HRMS (ESI): Calcd
for C24H20Br2O2Na+: 520.9728; found: 520.9726. Anal. Calcd for
Compound 9: To a mixture of 2,20-Cyanomethoxy-1,10-binaphyl
(1.29 g, 3.55 mmol) in dry THF was added dropwise BH3 (1M in
THF, 28 mL) under argon at 0 °C. The mixture was heated at reflux
for 1.5 h. 20 mL of 3 N HCl was carefully added after cooling. The
mixture was heated at reflux for 3 h then concentrated. 150 mL
of distilled water was added, pH was adjusted to 10 with 3 N
NaOH. The mixture was extracted with 3 ꢀ 100 mL of CH2Cl2.
The organic phases were combined, extracted with 2 ꢀ 100 mL of
distilled water, 100 mL brine, dried over MgSO4, filtered and
evaporated to dryness to give 6 as a white foam (1.3 g, 97%).
0.8 mL of oxalyl chloride (9.3 mmol) was added dropwise to a solu-
tion of 2.06 g of 2,3-bis(benzyloxy)benzoic acid 4 (6.1 mmol) in
CH2Cl2 (30 mL). After adding a drop of DMF, the mixture was stir-
red until the end of HCl release. After evaporation of solvents and
residual oxalyl chloride, the residue was dissolved in dry CH2Cl2
and added dropwise to a solution of 6 (1.13 g, 3 mmol) and
C24H20Br2O2: C, 57.63; H, 4.03; Br, 31.95; O, 6.40. Found: C,
57.85; H, 4.00.
700 mg of 1 (1.4 mmol) and 15 mL of triethylphosphite were
stirred and heated to 165 °C for 16 h. The volatile components
were removed by distillation in vacuo, with the temperature rising
from ambient to 100 °C, to give a practically quantitative yield of 2
mixed with P(OEt)3 as a yellow oil in about 70% purity (1H NMR
analysis); the product was used without further purification. 1H
NMR (CDCl3, 300 MHz, 25 °C) d (ppm): 7.87 (d, J = 9.0 Hz, 2H, Ar–
H), 7.78 (d, J = 8.1 Hz, 2H, Ar–H), 7.36 (d, J = 9.0 Hz, 2H, Ar–H),
7.22–7.27 (m, 2H, Ar–H), 7.11–7.15 (m, 2H, Ar–H), 7.04 (d,
J = 8.1 Hz, 2H, Ar–H), 4.06–4.15 (m, 4H, O–CH2–CH2–P), 3.77–3.82
(m, 8H, P–O–CH2–CH3), 1.78–1.85 (m, 4H, O–CH2–CH2–P), 1.06–

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A. Leydier et al. / Tetrahedron Letters 52 (2011) 3973–3977
1.3 mL of triethylamine (9.2 mmol) in 30 mL of dry CH2Cl2. After
18 h under stirring, the mixture was washed with water
(2 ꢀ 50 mL), brine (50 mL), then dried over MgSO4 and evaporated
to dryness. The residue was purified by silica gel column chroma-
tography (EtOAc3/Cyclohexane 1) to give 7 (1.45 g, 48%) as a white
powder. 1H NMR (CDCl3, 300 MHz, 25 °C) d (ppm): 7.92 (d,
J = 9.2 Hz, 2H, Ar–H), 7.84 (d, J = 8.3 Hz, 2H, Ar–H), 7.38 (d,
J = 9.2 Hz, 2H, Ar–H), 7.22–7.30 (m, 4H, Ar–H), 7.18 (d, J = 8.3 Hz,
2H, Ar–H), 3.99 (m, 2H, O–CH2–CH2–NH2), 3.87 (m, 2H, O–CH2–
CH2–NH2), 2.62 (br s, 4H, O–CH2–CH2–NH2). 13C NMR (CDCl3,
75 MHz, 25 °C): 154.8 (Ar–C), 134.6 (Ar–C), 130.4 (Ar–CH), 129.9
(Ar–CH), 129.1 (Ar–CH), 127.3 (Ar–CH), 126.7 (Ar–CH), 124.5
(Ar–C), 119.0 (Ar–C), 115.9 (Ar–CH), 71.2, (CH2), 41.2 (CH2) HRMS
(ESI): calcd for C24H24N2O2: 372.1838; found: 372.1835. Anal.
Calcd for C24H24N2O2: C, 77.39; H, 6.49; N, 7.52; O, 8.59. Found:
C, 77.12; H, 6.71; N, 7.23.
1.017 g of 7 (1 mmol) and 100 mg of Pd/C (5%) in 25 mL of THF
were stirred under 1 atm of H2. After 36 h, the mixture was filtered
on celite, evaporated to dryness to give 8 (633 mg, 98%) as a grey
foam. 1H NMR (CDCl3, 300 MHz, 25 °C) d (ppm): 7.51–7.63 (m,
4H, Ar–H), 6.80–7.31 (m, 34H, Ar–H), 4.99 (s, 4H, O–CH2–Ar),
4.58 (AB d, 2H, 2J(H,H) = 10.9 Hz, 2H, O–CH2–Ar), 4.51 (AB d,2H,
2J(H,H) = 10.7 Hz, 2H, O–CH2–Ar), 3.72 (t, J = 5.3 Hz, 4H, O–CH2–
CH2–NH), 3.10 (m, 4H, O–CH2–CH2–NH) 13C NMR (CDCl3,
75 MHz, 25 °C): 165.7 (Ar–C), 154.1 (Ar–C), 152.2 (Ar–C), 146.8
(Ar–C), 137.1 (Ar–C), 136.8 (Ar–C), 134.3 (Ar–C), 129.9 (Ar–CH),
129.8 (Ar–C), 129.1 (Ar–CH), 129.0 (Ar–CH), 128.8 (Ar–CH), 128.7
(Ar–CH), 128.6 (Ar–CH), 128.4 (Ar–CH), 128.3 (Ar–CH), 128.2
(Ar–CH), 128.1 (Ar–CH), 126.7 (Ar–CH), 125.6 (Ar–C), 124.6 (Ar–
CH), 124.1 (Ar–CH) 123.2 (Ar–C), 120.7 (Ar–C), 116.9 (Ar–CH),
133.9 (Ar–C), 133.7 (Ar–C), 130.5 (Ar–CH), 130.2 (Ar–CH), 129.9
(Ar–C), 129.6 (Ar–CH), 128.9 (Ar–CH), 128.5 (Ar–CH), 127.2 (Ar–
CH), 125.3 (Ar–CH), 124.6 (Ar–CH), 124.4 (Ar–CH), 120.9 (Ar–C),
116.2 (Ar–CH), 105.8 (Ar–CH), 79.33 (CH2), 68.3 (CH2), 39.6 (CH2)
HRMS (ESI): calcd for
849.2901. Anal. Calcd for C50H42N2O8: C, 72.63; H, 5.12; N, 6.78;
O, 15.48. Found: C, 72.61; H, 5.31; N, 6.60.
C
50H42N4O8Na+: 849.2900; found:
774 mg of 10 (0.936 mmol) were added in 25 mL 32% HCl mixed
with 65 mL Acetic. After 96 h under stirring, the mixture was evap-
orated, 100 mL water were added. The mixture was washed with
CH2Cl2 (3 ꢀ 50 mL).The combined organic layers were washed
with water (3 ꢀ 50 mL), brine (50 mL), then dried over MgSO4
and evaporated to dryness to give 11 (593 mg, 98%) as a yellow
foam. 1H NMR (CDCl3, 300 MHz, 25 °C) d (ppm): 8.50 (br s, 2H,
OH), 7.93 (br s, 2H, NH), 7.70 (d, J = 8.9 Hz, 2H, Ar–H), 7.64 (d,
J = 7.9 Hz, 2H, Ar–H), 7.01–7.31 (m, 10H, Ar–H), 6.95 (d,
J = 8.1 Hz, 2Ar–H), 6.85 (d, J = 8.7 Hz, 2Ar–H), 3.91–4.07 (m, 4H,
O–CH2–CH2–NH), 3.40 (br s, 4H, O–CH2–CH2–NH). 13C NMR
(CDCl3, 75 MHz, 25 °C) d (ppm): 159.1 (C=O), 157.2 (Ar–C), 153.9
(C@O), 136.9 (Ar–C), 134.7 (Ar–CH), 134.3 (Ar–C), 130.1 (Ar–CH),
130.0 (Ar–CH), 128.3 (Ar–C), 126.9 (Ar–CH), 125.4 (Ar–CH), 124.5
(Ar–CH), 121.4 (Ar–C), 116.7 (Ar–CH), 116.6 (Ar–CH), 113.0 (Ar–
CH), 68.9 (CH2), 40.1 (CH2). HRMS (ESI): calcd for C36H30N4O8Na+:
669.1961; found: 669.1961. Anal. Calcd for C36H30N4O8: C, 66.87;
H, 4.68; N, 8.66; O, 19.79. Found: C, 66.66; H, 4.82; N, 8.29.
Acknowledgements
We thank Dr. Bouchu, Genevieve Herault and Marie-Christine
Duclos for analytical assistance. This work was supported by a pro-
gram of Interdisciplinary Research called ‘Nuclear and Environ-
mental Toxicology, Tox-Nuc-E’ funded by the Commissariat à
l’Energie Atomique (CEA) and Centre National pour la Recherche
Scientifique (CNRS).
115.9 (Ar–CH), 76.2 (CH2), 71.5 (CH2), 68.4 (CH2), 39.4 (CH2).
+
HRMS (ESI): calcd for
C
66H57N2O8
:
1005.4115; found:
1005.4118. Anal. Calcd for C66H56N2O8: C, 78.86; H, 5.62; N, 2.79;
O, 12.73. Found: C, 79.14; H, 5.53; N, 2.60.
Compound 8: (183 mg, 0.27 mmol) in 96% H2SO4 (2 mL) was stir-
red at 50 °C for 16 h. The mixture was then allowed to cool to room
temperature, poured in Et2O (50 mL). The resulting precipitate was
filtered off under argon and dried under vacuum to give 9 as a hygro-
scopic green powder (200 mg, 75%). 1H NMR (D2O, 300 MHz, 25 °C) d
(ppm): 8.07 (d, J = 9 Hz, 2H, Ar–H), 7.48–7.58 (m, 6H, Ar–H), 7.33 (d,
2H, J = 2.4 Hz), 7.14 (d, J = 9 Hz, 2H, Ar–H), 6.80 (d, J = 2.4 Hz, 2H, Ar–
H), 4.02–4.08 (m, 4H, CH2), 3.31–3.37 (m, 4H, CH2). 13C NMR (D2O,
75 MHz, 25 °C) d (ppm): 171.6 (C@O), 158.9 (Ar–C), 155.9 (Ar–C),
138.1 (Ar–C), 134.8 (Ar–C), 132.5 (Ar–C), 131.9 (Ar–CH), 128.7 (Ar–
C), 127.8 (Ar–C), 126.5 (Ar–CH), 126.3 (Ar–CH), 123.7 (Ar–C), 123.0
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(Ar–CH), 119.9 (Ar–C), 118.3 (Ar–CH), 114.3 (Ar–CH), 112.6 (Ar–
+
CH), 69.2 (CH2), 39.0 (CH2) HRMS (ESI): calcd for C38H32N2NaO20S4
987.0323; found: 987.0319.
:
Compound 11: 0.9 mL of oxalyl chloride (10 mmol) was added
dropwise to a solution of 1.79 g of 5 (7.3 mmol) in CH2Cl2
(15 mL). After adding a drop of DMF, the mixture was stirred until
the end of HCl release. After evaporation of solvents and residual
oxalyl chloride, the residue was dissolved in dry CH2Cl2 and added
dropwise to a solution of 6 (1.3 g, 3.5 mmol) and 1.2 mL of trieth-
ylamine (8.5 mmol) in 30 mL of dry CH2Cl2. After 18 h under stir-
ring, the mixture was washed with water (2 ꢀ 50 mL), brine
(50 mL), then dried over MgSO4 and evaporated to dryness. The
residue was purified by silica gel column chromatography (EtOAc)
to give 10 (1.68 g, 58%) as a white powder. 1H NMR (CDCl3,
300 MHz, 25 °C) d (ppm): 7.75 (m, 4H, Ar–H), 7.16–7.33 (m, 16H,
Ar–H), 7.01–7.10 (m, 4H, Ar–H), 6.70 (dd, J = 1.5 Hz, 9.3 Hz, 2H,
Ar–H), 6.13 (t, J = 5.5 Hz, 2H, Ar–H), 5.84, (dd, J = 1.5 Hz, 6.78 Hz,
2H, Ar–H), 5.13 (d, J = 8.5 Hz, 1H, O–CH2–Ar), 5.08 (d, J = 8.5 Hz,
1H, O–CH2–Ar) 3.86 (m, 4H, O–CH2–CH2–NH), 3.22 (m, 4H, O–
CH2–CH2–NH). 13C NMR (CDCl3, 75 MHz, 25 °C) d (ppm): 160.4
(Ar–C), 158.8 (Ar–C), 153.4 (Ar–C), 142.8 (Ar–C), 138.4 (Ar–CH),
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