An efficient route for the synthesis of new analogues of polyaminocarboxylic acid incorporating O, N, and S atoms

Article abstract of DOI:10.1002/ejoc.200300459

We have synthesised three rigid polycarboxylated hexadentate ligands that differ only in the nature of their heteroatom, either oxygen (1), nitrogen (2), or sulfur (3). These compounds were obtained in four or five steps from substituted orthoanilines after protection/deprotection sequences. An aromatic backbone was chosen to stiffen the structure of the ligands and, thus, facilitate complexation (preorganization concept). A preliminary chelation test revealed a marked selectivity of the nitrogen-containing ligand for indium-111. In accordance with the hard and soft acid and base (HSAB) theory, the choice of ligand should result in notable differences in behaviour during complexation and, thus, augment selectivity with regard to the metal. Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2004.

Full text of DOI:10.1002/ejoc.200300459

FULL PAPER
An Efficient Route for the Synthesis of New Analogues of Polyaminocarboxylic
Acid Incorporating O, N, and S Atoms
[a,b]
Eric Benoist,[c] Jean-Francois Gestin,[b] Jean Claude Meslin,[a] and
´
Sebastien G. Gouin,
¸
David Deniaud*[a]
Keywords: Carboxylic acids / Chelating agents / O, N, S ligands / Synthesis design
We have synthesised three rigid polycarboxylated hexadent- lectivity of the nitrogen-containing ligand for indium-111. In
ate ligands that differ only in the nature of their heteroatom,
accordance with the hard and soft acid and base (HSAB) the-
either oxygen (1), nitrogen (2), or sulfur (3). These com- ory, the choice of ligand should result in notable differences
pounds were obtained in four or five steps from substituted
orthoanilines after protection/deprotection sequences. An
aromatic backbone was chosen to stiffen the structure of the
ligands and, thus, facilitate complexation (preorganization
concept). A preliminary chelation test revealed a marked se-
in behaviour during complexation and, thus, augment select-
ivity with regard to the metal.
( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2004)
Introduction
Oxygenated, nitrogenated, and sulfurated polydentate li-
gands that bear carboxylic (or phosphonic) acid functions
are known for their ability to complex transition and non-
transition metal cations.[1Ϫ6] According to the nature of the
metal used, many different applications can be considered,
most notably in medical fields. For example, gadolinium
complexes are employed as contrast agents in MRI and are
currently used in clinical practice.[7Ϫ11] Similarly, polyamin-
Figure 1. Ligands prepared in the study
These considerations, and our experience in the synthesis
ocarboxylic derivatives are classically used to complex of polyaminopolycarboxylated molecules,[28Ϫ33] led us to
radionuclides for diagnostic applications (e.g., the gamma develop three new analogous ligands (Figure 1), whose
emitters 111In, 64Cu, 67Ga, and 99mTc)[12Ϫ14] or in radioim- structures differ only in the nature of their heteroatom,
munotherapy (e.g., the alpha or beta emitters 90Y, 153Sm, which is either oxygen (1), nitrogen (2), or sulfur (3). Thus,
and 212Bi).[15Ϫ21] In all these applications, in vivo stability of as a function of the ‘‘hard/soft’’ nature of the metal, the
the ligandϪmetal complex is highly desirable. Such stability choice of ligand should lead to a notable differences in com-
requires ligands that are suitable for the chosen metal. plexation and, thus, increase the selectivity with regard to
Other examples include the use of polyaminocarboxylated the metal. Our ligands possess an aromatic ring to induce
ligands for trapping heavy metals, such as lead, cadmium, rigidity into the cavity and to facilitate complexation (most
and mercury.[22,23] Finally, there has been increasing interest notably by reducing the entropy of the reaction). It is
during the last ten years in using lanthanide complexes for known that a semi-rigid or rigid structure provides a signifi-
energy transfer processes in numerous photoluminescence cant increase for the stability of its complexes. In fact, rigid-
applications.[24Ϫ27]
ification of the molecular skeleton reduces the freedom of
donor atoms, and this spatial preorganisation is conducive
to more-efficient complexation.[34Ϫ38]
Polydentate ligands based on an aromatic design have
stable geometries and are also easily functionalisable, which
is an essential feature for grafting them onto any type of
support (e.g., antibody, peptide, or silica). This paper de-
scribes the synthesis of three potential hexadentate ligands
that are all derived from a substituted orthoaniline. The na-
ture of the heteroatom is responsible for the notable varia-
[a]
`
Laboratoire de Synthese Organique, UMR C.N.R.S. 6513,
´
Faculte des Sciences et des Techniques,
`
2 rue de la Houssiniere, BP 92208, 44322 Nantes Cedex 3,
France
[b]
[c]
´
INSERM U463, Chimie des bioconjugues,
9 quai Moncousu, 44093 Nantes Cedex, France
Laboratoire de Chimie Inorganique,
Bat. IIR1, 118, route de Narbonne, 31062 Toulouse Cedex,
France
Fax: (internat.) ϩ 33-2-51125402
E-mail: deniaud@chimie.univ-nantes.fr
878
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
DOI: 10.1002/ejoc.200300459
Eur. J. Org. Chem. 2004, 878Ϫ885

New Analogues of Polyaminocarboxylic Acids
FULL PAPER
tions in the syntheses. We also checked whether selectivity or deprotection in an acidic medium, which gave a benzimi-
during complexation was affected by the nature of the het- dazole quantitatively by intramolecular cyclisation.[30] The
eroatom. To do so, we performed a preliminary com- trialkylation of 8 with tert-butyl bromoacetate to give 9 pro-
plexation test using radioactive indium (111In).
ved to be difficult because it was necessary to avoid polyalk-
ylation as completely as possible.
Result and Discussion
1. Synthesis of Ligands
The synthesis of compound 1 was performed in four steps
with an overall yield of 65% (Scheme 1). The first step in-
volved a conventional dicyclohexylcarbodiimide-mediated
amide coupling in THF between N-carbobenzyloxyglycine
and ortho-aminophenol.[39] This coupling reaction was en-
tirely chemoselective; no acylation was observed to occur
on the oxygen atom. The benzyloxycarbonyl protecting
group was removed by the action of 10% palladium on
charcoal as a catalyst under a hydrogen atmosphere, which
gave 5[39] in quantitative yield without the need for further
purification.
Scheme 2. Synthesis of the intermediate 9. Reagents and conditions:
(a) DCC, Z-glycine, THF, reflux, 4 h; (b) EtOH, Pd/C 10%, H2,
room temp., 24 h; (c) BrCH2CO2tBu, K2CO3, KI, THF, 35 °C, 4
days
The best results were achieved in THF at 35 °C using
3.4 equivalents of alkylating agent. Thus, compound 9 was
obtained in 60% yield by minimising the formation of the
secondary products (10, 11, and 12) as much as possible
(Figure 2). Alkylation of the amide (compound 10, 15%)
occurred preferentially over double substitution of the aro-
matic amino group (compound 11, 7%).
Scheme 1. Synthetic route to ligand 1. Reagents and conditions:
(a) DCC, Z-glycine, THF, reflux, 4 h; (b) EtOH, Pd/C 10%, H2,
room temp., 18 h; (c) BrCH2CO2tBu, K2CO3, KI, CH3CN, room
temp., 24 h; (d) TFA, room temp., 24 h, then HCl (1 )
An alkylation reaction at ambient temperature using tert-
butyl bromoacetate in the presence of a catalytic amount of
potassium iodide and an excess of potassium carbonate in
acetonitrile[40,41] gave the trialkylated molecule 6 in 77%
yield. Final product 1 was obtained after hydrolysis of the
esters in neat trifluoroacetic acid at ambient temperature.
After 24 h of shaking, and then treatment with 1  HCl,
the triacid was precipitated as its corresponding hydrochlo-
ride salt as a white solid that was isolated in quantitative
yield simply by filtration.
Figure 2. Secondary products obtained during alkylation
The synthesis of 2, a nitrogenous homologue of 1, began
in the same manner from phenylene-1,2-diamine
(Scheme 2). Monosubstitution by N-carbobenzyloxyglycine
The structure of compound 9 was determined unequivo-
1
provided intermediary 7 in 82% yield.[42] Deprotection of cally by complementary 2D H NMR spectroscopy tech-
the glycine amino group occurred in this case using hydro- niques (COSY, HMQC, and HMBC). At this stage, the hy-
gen gas under pressure to give 8 in 98% yield. This method drolysis of the tert-butyl esters using trifluoroacetic
proved to be more efficient than the use of cyclohexene[39,43] acid[44,45] did not lead to the formation of the expected
Eur. J. Org. Chem. 2004, 878Ϫ885
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 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
879

S. G. Gouin, E. Benoist, J.-F. Gestin, J. C. Meslin, D. Deniaud
FULL PAPER
compound 2, but instead it gave a heterocyclic molecule
having a molar mass that corresponded to the loss of a
water molecule. The structure of compound 13, which pos-
sesses three carboxylic acid functions, was revealed un-
equivocally by the action of diazomethane,[46] which pro-
vided the corresponding methyl ester 14 (Scheme 3). Be-
cause no such intramolecular cyclisation was observed with
the corresponding oxygenated and sulfurated compounds,
it is logical to suppose that the acidic medium favoured at-
tack on the carbonyl group by the electron lone-pair of the
aromatic amino group. The benzoimidazole structure pro-
posed for 13, and confirmed by spectroscopic analyses, was
probably obtained according to the mechanism shown in
Scheme 5.
Scheme 4. Synthesis of ligand 2. Reagents and conditions:
(a) BrCH2CO2Bn, K2CO3, KI, THF, 35 °C, 3 days; (b) MeOH,
Pd(OH)2, H2, room temp., 1.5 h
the conditions described for the synthesis of 9 (Scheme 4).
The benzyl groups were then removed by hydrogenolysis
using Pearlman’s catalyst [Pd(OH)2] in methanol.[47] Ligand
2 was obtained in this manner as a white solid in an overall
yield of 40%.
The preparation of the sulfurated ligand 3 was conducted
in a manner different from that of the other two ligands.
The peptide coupling between ortho-aminothiophenol and
N-carbobenzyloxyglycine allowed compound 16 to be iso-
lated in a modest yield of 28% (probably because of com-
petitive acylation on the sulfur atom). To overcome this
problem, the sulfur atom (the most nucleophilic site) was
alkylated initially using tert-butyl bromoacetate; product 17
was isolated in 76% yield (Scheme 5). Despite total chemo-
Scheme 3. Formation of benzoimidazole 13. Reagents and con-
ditions: (a) MeOH, 6  HCl, 60 °C, 4 days; (b) MeOH, CH2N2,
5 min
The synthesis of compound 2 was then resumed from 8 selectivity, the by-products 18 (5%) and 19 (8%) were ob-
by using benzyl bromoacetate as the alkylating agent. This served to result from intramolecular attack by the nitrogen
approach introduces ester functions that are cleavable by atom on the ester carbonyl group. Once the thiol was pro-
hydrogenolysis in a neutral medium. The intermediate 15 tected, it was reacted with Z-glycine. The best results were
was then obtained in a relatively modest yield of 50% under obtained by activating the carboxylic acid function of gly-
Scheme 5. Synthesis of intermediate 20. Reagents and conditions: (a) Z-glycine, DCC, THF, room temp., 4 h; (b) BrCH2CO2tBu, K2CO3,
KI, THF, 60 °C, 18 h; (c) (COCl)2, DMF, Z-glycine, CH2Cl2, 0 °C, 2 h then 17, Et3N, CH2Cl2, room temp., 18 h
880
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Eur. J. Org. Chem. 2004, 878Ϫ885

New Analogues of Polyaminocarboxylic Acids
FULL PAPER
˚
cine as its acid chloride prepared in situ by the addition cause its size (R ϭ 0.80 A) and coordination geometry seem
of oxalyl chloride in the presence of a catalytic amount of suited for complexation with the O-, N-, and S-containing
DMF.[48Ϫ50] After peptide coupling on 17, the intermediate molecules. Moreover, we chose indium-111 because its
20 was isolated in 68% yield.
physical properties [half-life of 67.4 h, γ emission with an
The next step — the selective deprotection of the amino energy of 173 keV (83%), 247 keV (94%)] allow the prep-
group — gave poor results, regardless of the conditions aration of complexes that can be used in immunoscintigra-
used. Classically, heterogeneous catalysts, such as palladium phy, which is a widely used diagnostic method. To form the
on charcoal, are inactivated by slight traces of sulfur deriva- 111In-chelated complexes, a fixed quantity (13 µCi) of an
tives. Thus, it was not possible to obtain compound 22 111In stock solution was added to each chelating agent (1,
using catalytic hydrogenation. Lewis acids, which have been 2, and 3; 1 or 10 equiv). The volume of each sample was
used previously to deprotect benzyloxycarbonyl groups, adjusted to 150 mL with 0.1  sodium acetate, and the solu-
also gave unsatisfactory results.[51,52] We decided to avoid tions were incubated at 37 °C for 1 h. The final pH of each
this step by repeating the synthesis procedure using the gly- solution ranged from 5.6 to 5.8, with final 111In concen-
cine derivative whose nitrogen atom is protected by the 9- trations of 48 pM. The chelation yield was measured on a
fluorenylmethoxycarbonyl (Fmoc) group, which can be Phosphorimager apparatus after TLC on cellulose plates.
cleaved readily in basic media (Scheme 6). The acylation re-
The experimental results, summarised in Table 1, display
action gave the intermediate 21 in 93% yield. The Fmoc a marked difference in the reactivity of the three ligands.
function was then removed by the action of piperidine in Indeed, only the nitrogen-containing ligand 2 is able to
dichloromethane,[53] which led to the primary amine 22. Be- complex efficiently with indium: no chelated indium was
cause this synthon proved relatively unstable on the col- observed for the oxygen- and sulfur-containing molecules,
umn, it seemed preferable to cleave the Fmoc group and even when using 1000 equivalents of the ligands. Therefore,
allow the reaction mixture to be reacted directly with tert- this first test clearly demonstrates that the selectivity of
butyl bromoacetate. Thus, the triester 23 was obtained from compound 2 toward indium is related to the nature of its
21 in 75% yield. The corresponding triacid was isolated heteroatom.
quantitatively by hydrolysis of the tert-butyl groups in neat
trifluoroacetic acid at ambient temperature. Thus, ligand 3
was synthesised, as its trifluoroacetate salt, in five steps
with an overall yield of 53%.
Table 1. Effect of ligand concentration on the efficiency of chelator-
labelling ([111In] ϭ 1.5 nmol·mLϪ1; reaction period ϭ 1 h; pH ϭ
5.6Ϫ5.8; temperature ϭ 37 °C; final chelation volume ϭ 150 µL;
0.1  sodium acetate buffer)
%
111In-chelated
Ligand 2
Mol equivalents
Ligand 1
Ligand 3
1
10
0
0
57
75
0
0
Conclusion
We have synthesised three new hexacoordinate polydent-
ate ligands that differ only in the nature of their het-
eroatom. The three analogues, 1, 2, and 3, which contain
O, NH, and S units, respectively, were synthesised in four
or five steps in yields of 65, 40, and 53%, respectively. A
preliminary complexation test using radioactive indium
demonstrated differences in the behaviour of the three ana-
logues. Indeed, only ligand 2, which incorporates a nitrogen
atom, is able to chelate this metal efficiently. The com-
plexation properties of this molecule with indium still need
to be quantified (e.g., its stability in serum and its com-
plexation constant). To establish a correlation between the
nature of the ligand and the HSAB theory, a range of more
or less hard metals must be tested. This study should allow
us to gain greater insight into the potential of such chelates.
Scheme 6. Synthetic route to ligand 3. Reagents and conditions:
(a) (COCl)2, DMF, Fmoc-glycine, THF, 0 °C, 30 min, then 17, N-
ethyldiisopropylamine, THF, room temp., 1 h; (b) piperidine,
CH2Cl2, room temp., 20 min; (c) BrCH2CO2tBu, K2CO3, KI, THF,
70 °C, 5 h; (d) TFA, room temp., 2 days
2. Testing Complexation
Preliminary complexation tests were performed with all Depending on the end application, extra functional groups
three ligands 1, 2, and 3 using indium-111, which appears may be added readily to ligands by introducing an amino
to be an appropriate isotope for the first chelation test be- function via a nitro group under mild conditions.[54]
Eur. J. Org. Chem. 2004, 878Ϫ885
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881

S. G. Gouin, E. Benoist, J.-F. Gestin, J. C. Meslin, D. Deniaud
FULL PAPER
to a solution of 2-amino-N-(2-aminophenyl)ethanamide 8 (0.15 g,
0.91 mmol) in freshly distilled THF (10 mL). tert-Butyl bromoacet-
ate (452 µL, 605 mg, 3.1 mmol) was then, added slowly by syringe
and the resulting solution was heated at 35 °C for 4 d. After cooling
to room temperature, the mixture was concentrated to dryness. The
resulting residue was partitioned between CH2Cl2 (30 mL) and
water (20 mL). The organic extract was dried (MgSO4) and filtered
and then the solvents were evaporated. The residue was purified by
flash chromatography on silica gel (CH2Cl2/hexane/Et3N, 5:93:2)
to give 9 as a colourless oil (280 mg, 0.55 mmol, 60%). Without
modifying the elution conditions, compounds 11, 10, and 12 were
isolated in that order. IR (KBr): ν˜ ϭ 3288, 2978, 1733, 1368, 1150
cmϪ1. 1H NMR (CDCl3, 200 MHz, 25 °C): δ ϭ 1.45 (s, 9 H), 1.47
(s, 18 H), 3.53 (s, 6 H), 3.83 (d, J ϭ 5.7 Hz, 2 H), 5.13 (m, 1 H),
6.59 (d, J ϭ 7.9 Hz, 1 H), 6.77 (t, J ϭ 7.5 Hz, 1 H), 7.10 (t, J ϭ
7.9 Hz, 1 H), 7.43 (d, J ϭ 7.9 Hz, 1 H), 9.62 (br. s, 1 H) ppm. 13C
NMR (CDCl3, 50 MHz, 25 °C): δ ϭ 28.3(9), 46.9, 57.4(2), 59.5,
81.7, 82.1(2), 112.2, 118.1, 124.0, 125.2, 126.8, 141.3, 170.2, 170.4,
170.8(2) ppm. MS: m/z ϭ 508 [M ϩ H]ϩ (100), 394, 246, 202.
HRMS (LSIMS): calcd. for C26H42N3O7 [M ϩ H]ϩ m/z ϭ
508.3023, found 508.3021.
Experimental Section
General Remarks: All reagents were purchased either from Acros
Organics or SigmaϪAldrich. The C.N.R.S. Analysis Laboratory
(Vernaison) performed the elemental analyses. Column chromatog-
raphy was conducted over silica gel 60 (40Ϫ63 µm) purchased from
E. Merck. Thin-layer chromatography was performed on 0.5 mm
ϫ 20 cm ϫ 20 cm E. Merck silica gel plates (60 F-254). Melting
points were measured using a Reichert microscope and are uncor-
1
rected. The 13C and H NMR spectra were recorded at room tem-
perature using Bruker AC 200 and ARX 400 spectrometers. Chemi-
cal shifts (δ) are given in ppm downfield from tetramethylsilane as
internal standard, and coupling constants (J) are given in Hertz
(Hz). Multiplicities were listed as s (singlet), d (doublet), t (triplet),
q (quadruplet), and m (multiplet). Mass spectra were determined
using HewlettϪPackard 5989 and NERMAG R 10Ϫ10 mass spec-
trometers. HRMS spectra were recorded at the CRMPO (Centre
´
regional de Mesures physiques de lЈouest de Rennes). IR spectra in
the range 4000Ϫ400 cmϪ1 were obtained using a Bruker Vector 22
spectrometer. All chemicals were reagent grade and used without
further purification. Tetrahydrofuran was freshly distilled from Na/
benzophenone ketyl, while dichloromethane was distilled over
CaH2. All reactions were carried out under an N2 atmosphere.
Di-tert-butyl N-[N-o-(tert-Butoxycarbonylmethylamino)phenyl-N-
tert-butoxycarbonylmethylcarbamoylmethyl]iminodiacetate
Colourless oil (87 mg, 0.14 mmol, 15%). IR (KBr): ν˜ ϭ 3337, 2978,
2933, 1739, 1671, 1606, 1524, 1458, 1368, 1224, 1155 cmϪ1 1H
(10):
Di-tert-butyl
N-[N-o-(tert-Butoxycarbonylmethoxy)phenylcarba-
moylmethyl]iminodiacetate (6): Potassium carbonate (8.31 g,
60.2 mmol) and potassium iodide (0.20 g, 1.2 mmol) were added to
a solution of 2-amino-N-(2-hydroxyphenyl)ethanamide 5 (1.00 g,
6.02 mmol) in freshly distilled CH3CN (30 mL). tert-Butyl bromo-
acetate (2.92 mL, 3.9 g, 20 mmol) was then added dropwise and the
resulting solution was stirred at room temperature for 24 h. The
mixture was filtered and the filtrate was concentrated to dryness.
The resulting residue was partitioned between CH2Cl2 (100 mL)
and water (80 mL). The organic extract was dried (MgSO4) and
filtered and then the solvents were evaporated. The residue was
purified by flash chromatography on silica gel (CH2Cl2/heptane,
1:1) to give 6 as a yellow oil (2.35 g, 4.63 mmol, 77%). IR (KBr):
ν˜ ϭ 3276, 2976, 1750, 1737, 1685, 1601, 1535, 1295, 1240, 1146,
.
NMR (CDCl3, 200 MHz, 25 °C): δ ϭ 1.41 (s, 18 H), 1.43 (s, 9 H),
1.46 (s, 9 H), 3.43 (m, 6 H), 3.83 (d, J ϭ 6.2 Hz, 2 H), 3.94 (d, J ϭ
16.8 Hz, 1 H), 4.28 (d, J ϭ 16.8 Hz, 1 H), 6.01 (t, J ϭ 8.1 Hz, 1
H), 6.52 (d, J ϭ 8.1 Hz, 1 H), 6.67 (t, J ϭ 7.5 Hz, 1 H), 7.15 (m, 2
H) ppm. 13C NMR (CDCl3, 50 MHz, 25 °C): δ ϭ 28.2(12), 45.9(2),
51.8(2), 55.4(2), 56.2(4), 80.8(2), 81.6, 82.1, 111.4, 117.5, 127.8,
129.3, 129.8, 144.6, 169.4, 169.9, 170.7(2), 172.0 ppm. MS: m/z ϭ
622 [M ϩ H]ϩ (100), 508, 380, 246. HRMS (LSIMS): calcd. for
C32H52N3O9 [M ϩ H]ϩ m/z ϭ 622.3704, found 622.3706.
Di-tert-butyl N-[N-o-(Di-tert-butoxycarbonylmethylamino)phenyl-
carbamoylmethyl]iminodiacetate (11): Colourless oil (40 mg,
0.06 mmol, 7%). IR (KBr): ν˜ ϭ 3282, 2978, 2931, 1738, 1685, 1589,
1
759 cmϪ1. H NMR (CDCl3, 200 MHz, 25 °C): δ ϭ 1.42 (s, 9 H),
1
1522, 1457, 1368, 1223, 1147 cmϪ1. H NMR (CDCl3, 200 MHz,
1.43 (s, 18 H), 3.51 (s, 6 H), 4.56 (s, 2 H), 6.75 (m, 1 H), 6.98 (m,
2 H), 8.35 (m, 1 H), 10.03 (br. s, 1 H) ppm. 13C NMR (CDCl3,
50 MHz, 25 °C): δ ϭ 28.1(9), 56.5(2), 59.1, 66.9, 81.5(2), 82.2,
112.3, 120.6, 122.1, 123.7, 128.4, 147.5, 167.8, 169.3, 170.0(2) ppm.
MS: m/z ϭ 509 [M ϩ H]ϩ (100), 395. C26H40N2O8: calcd. C 61.42,
H 7.87, N 5.51; found C 61.39, H 7.93, N 5.52.
25 °C): δ ϭ 1.36 (s, 18 H), 1.44 (s, 18 H), 3.55 (s, 2 H), 3.60 (s, 4
H), 3.88 (s, 4 H), 7.00 (td, J ϭ 7.6, 1.6 Hz, 1 H), 7.13 (td, J ϭ 7.9,
1.5 Hz, 1 H), 7.41 (dd, J ϭ 7.6, 1.5 Hz, 1 H), 8.40 (dd, J ϭ 7.9,
1.6 Hz, 1 H), 10.34 (s, 1 H) ppm. 13C NMR (CDCl3, 50 MHz, 25
°C): δ ϭ 28.2(6), 28.3(6), 55.8(4), 56.4(4), 58.8(2), 81.2(2), 81.4(2),
119.8, 123.5, 125.6, 125.9, 135.0, 139.0, 169.7(2), 170.1(3) ppm.
MS: m/z ϭ 622 [M ϩ H]ϩ (100), 508, 246, 147. HRMS (LSIMS):
calcd. for C32H52N3O9 [M ϩ H]ϩ m/z ϭ 622.3704, found 622.3707.
N-[N-o-(Carboxymethoxy)phenylcarbamoylmethyl]iminodiacetic
Acid Hydrochloride (1): Compound 6 (0.6 g, 1.18 mmol) was stirred
for 24 h at room temperature in trifluoroacetic acid (5 mL) and
then the solution was concentrated to dryness. The resulting residue
was precipitated by trituration with 1  hydrochloric acid to afford
Di-tert-butyl N-(N-o-Aminophenylcarbamoylmethyl)iminodiacetate
(12): Colourless oil (18 mg, 0.05 mmol, 5%). IR (KBr): ν˜ ϭ 3285,
2977, 2933, 1730, 1685, 1526, 1459, 1368, 1227, 1147 cmϪ1 1H
.
a
white amorphous solid (0.401 g, 1.18 mmol, 100%). M.p.
NMR (CDCl3, 200 MHz, 25 °C): δ ϭ 1.47 (s, 18 H), 3.51 (s, 6 H),
198Ϫ200 °C. IR (KBr): ν˜ ϭ 3371, 1731, 1682, 1559, 1351, 1247
6.78 (m, 2 H), 7.01 (m, 1 H), 7.51 (m, 1 H), 9.70 (s, 1 H) ppm. 13
C
1
cmϪ1. H NMR ([D6]DMSO, 200 MHz, 25 °C): δ ϭ 3.49 (s, 2 H),
NMR (CDCl3, 50 MHz, 25 °C): δ ϭ 28.3(6), 57.4(2), 59.7, 82.2(2),
117.2, 118.9, 124.2, 126.3, 139.8 (2), 169.6, 170.8(2) ppm. MS:
m/z ϭ 393 (Mϩ·), 236, 146, 121, 57. HRMS (LSIMS): calcd. for
C20H32N3O5 [M ϩ H]ϩ m/z ϭ 394.2342, found 394.2345.
3.58 (s, 4 H), 4.73 (s, 2 H), 6.98 (m, 3 H), 8.19 (d, J ϭ 6.4 Hz, 1
H), 9.94 (s, 1 H) ppm. 13C NMR ([D6]DMSO, 50 MHz, 25 °C):
δ ϭ 54.8(2), 58.4, 65.3, 112.5, 119.6, 121.1, 123.6, 127.6, 147.2,
168.6, 170.0, 171.8(2) ppm. MS (LSIMSϩ): m/z ϭ 362.9 [M ϩ
Na]ϩ (100), 378.9 [M ϩ K]ϩ. MS (LSIMSϪ): m/z ϭ 339.1 [M Ϫ
H]Ϫ (100), 361.1 [M ϩ Na Ϫ 2H]; C14H17ClN2O8: calcd. C 44.62,
H 4.24, N 7.43; found C 44.89, H 4.14, N 7.35.
N-(1-Carboxymethylbenzimidazol-2-ylmethyl)iminodiacetic
Acid
(13): 6  Hydrochloric acid (18 mL) was added dropwise to a mix-
ture of 9 (0.6 g, 1.18 mmol) in MeOH (12 mL). The solution was
heated at 60 °C and stirred for 2 days. The mixture was concen-
trated in vacuo, 6  hydrochloric acid (20 mL) was added, and the
solution was heated at 60 °C for 2 days. The water was evaporated
Di-tert-butyl
N-[N-o-(tert-Butoxycarbonylmethylamino)phenyl-
carbamoylmethyl]iminodiacetate (9): Potassium carbonate (1.28 g,
9.3 mmol) and potassium iodide (0.048 g, 0.29 mmol) were added
882
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2004, 878Ϫ885

New Analogues of Polyaminocarboxylic Acids
FULL PAPER
to give triacid 13 as a hygroscopic yellow powdery solid that was
dried under vacuum and kept under a nitrogen atmosphere
(381 mg, 1.18 mmol, 100%). M.p. 108Ϫ110 °C. IR (KBr): ν˜ ϭ
Ϫ H]ϩ, 320 (100), 302, 276, 232. C14H17N3O7: calcd. C 49.56, H
5.05, N 12.38; found C 49.74, H 5.16, N 12.59.
N-o-Mercaptophenyl-2-benzoxycarbonylaminoethanamide (16): o-
Aminothiophenol (0.25 g, 2 mmol) was added into a solution of N-
(benzyloxycarbonyl)glycine (0.418 g, 2 mmol) and N,NЈ-dicyclo-
hexylcarbodiimide (0.446 g, 2 mmol) in THF (8 mL) and the re-
sulting mixture was stirred for 4 h at room temperature under a
nitrogen atmosphere. The insoluble N,NЈ-dicyclohexylurea was fil-
tered off and the filtrate was concentrated to dryness. The resulting
solid was diluted with EtOAc (5 mL) and heated under reflux for
5 min. The resulting precipitate was filtered off to give compound
16 as a white solid that was dried under vacuum (0.185 g,
0.56 mmol, 28%). M.p. 134Ϫ136 °C. IR (KBr): ν˜ ϭ 3352, 3265,
1700, 1681, 1538, 1289 cmϪ1. 1H NMR ([D6]DMSO, 200 MHz, 25
°C): δ ϭ 3.38 (br. s, 1 H), 3.87 (d, J ϭ 6.0 Hz, 2 H), 5.07 (s, 2 H),
7.47 (m, 9 H), 7.68 (t, J ϭ 6.0 Hz, 1 H), 9.77 (s, 1 H) ppm. 13C
NMR ([D6]DMSO, 50 MHz, 25 °C): δ ϭ 43.9, 65.6, 125.5, 126.4,
127.2, 127.8(3), 128.4(2), 129.5, 130.6, 136.0, 137.0, 156.6,
168.7 ppm. MS: m/z ϭ 317 [M ϩ H]ϩ (100), 209. C16H16N2O3S:
calcd. C 60.74, H 5.10, N 8.85; found C 60.82, H 4.98, N 8.62.
3424, 2937, 1735, 1621, 1529, 1465, 1412, 1219 cmϪ1 1H NMR
.
(D2O, 200 MHz, 25 °C): δ ϭ 3.63 (s, 4 H), 4.48 (s, 2 H), 5.45 (s, 2
H), 7.57 (m, 2 H), 7.70 (m, 2 H) ppm. 13C NMR (D2O, 50 MHz,
25 °C): δ ϭ 50.5, 53.9, 62.3(2), 113.8, 121.9, 126.1, 126.7, 138.9,
144.3, 156.1, 178.7, 182.6(2) ppm. MS (LSIMSϩ): m/z ϭ 322.0 [M
ϩ H]ϩ (100), 344.1 [M ϩ Naϩ]. MS (LSIMSϪ): m/z ϭ 320.2 [M
Ϫ H]Ϫ (100), 342.1 [M ϩ Na Ϫ H].
Dimethyl N-(1-Methoxycarbonylmethylbenzimidazol-2-ylmethyl)-
iminodiacetate (14): A solution of 13 (0.03 g, 0.093 mmol) in
MeOH (1 mL) was treated with an excess of diazomethane (CAU-
TION), and the reaction mixture was stirred for 5 min at room
temperature. The solution was concentrated under reduced pressure
to afford the trimethyl ester 14 as an oil (0.034 mg, 0.093 mmol,
100%). IR (KBr): ν˜ ϭ 2955, 1751, 1734, 1521, 1465, 1419, 1208
cmϪ1. 1H NMR (CDCl3, 200 MHz, 25 °C): δ ϭ 3.48 (s, 4 H), 3.69
(s, 6 H), 3.76 (s, 3 H), 4.22 (s, 2 H), 5.46 (s, 2 H), 7.26 (m, 4 H)
ppm. 13C NMR (CDCl3, 50 MHz, 25 °C): δ ϭ 45.2, 51.7, 51.8(2),
52.7, 54.5(2), 109.1, 120.1, 122.5, 123.4, 136.3, 142.3, 150.8, 168.9,
171.1(2) ppm. MS: m/z ϭ 364 [M ϩ H]ϩ (100), 204. HRMS
(LSIMS): calcd. for C17H22N3O6 [M ϩ H]ϩ m/z ϭ 364.1509,
found 364.1513.
tert-Butyl o-Aminophenylsulfanyl Acetate (17): Potassium carbon-
ate (6.63 g, 47.9 mmol) and potassium iodide (0.025 g, 0.15 mmol)
were added to a solution of o-aminothiophenol (1 g, 8 mmol) in
freshly distilled THF (40 mL). After stirring the mixture for 15 min,
tert-butyl bromoacetate (1.18 mL, 8 mmol) was added dropwise
under nitrogen. The reaction mixture was kept at 60 °C over a
period of 18 h prior to cooling to room temperature, filtration, and
concentration under reduced pressure. The resulting residue was
partitioned between CH2Cl2 (80 mL) and water (80 mL). The or-
ganic extract was dried (MgSO4) and filtered and then the solvents
were evaporated. The residue was purified by flash chromatography
on silica gel (CH2Cl2/hexane/Et3N, 5:93:2) to give 19 (178 mg,
0.64 mmol, 8%) and 17 as a colourless oil (1.45 g, 6 mmol, 76%),
and then 18 (26 mg, 0.16 mmol, 5%) by using CH2Cl2/Et3N (98:2)
Dibenzyl N-[N-o-(Benzoxycarbonylmethylamino)phenylcarbamoyl-
methyl]iminodiacetate (15): Potassium carbonate (1.84 g, 13 mmol)
and potassium iodide (0.070 g, 0.422 mmol) were added to a solu-
tion of 2-amino-N-(2-aminophenyl)ethanamide
8
(0.217 g,
1.315 mmol) in freshly distilled THF (15 mL). Benzyl bromoacetate
(690 µL, 994 mg, 4.34 mmol) was then added dropwise and the
resulting solution was heated at 35 °C for 3 days under argon. After
cooling to room temperature, the mixture was concentrated to dry-
ness. The resulting residue was partitioned between CH2Cl2
(45 mL) and water (30 mL). The organic extract was dried (MgSO4)
and filtered and then the solvents were evaporated. The residue was
purified by flash chromatography on silica gel (CH2Cl2) to give 15
as a colourless oil (400 mg, 0.656 mmol, 50%). IR (KBr): ν˜ ϭ 3288,
as the eluent. IR (KBr): ν˜ ϭ 3456, 3357, 1722, 1298, 1137 cmϪ1
.
1H NMR (CDCl3, 200 MHz, 25 °C): δ ϭ 1.39 (s, 9 H), 3.39 (s, 2
H), 6.70 (m, 2 H), 7.13 (td, J ϭ 1.6, 8.1 Hz, 1 H), 7.44 (dd, J ϭ
1.6, J ϭ 7.6 Hz, 1 H) ppm. 13C NMR (CDCl3, 50 MHz, 25 °C): δ ϭ
30.0(3), 38.2, 81.8, 115.1(3), 116.7, 118.5, 130.5(3), 136.6, 148.7,
169.4 ppm. MS: m/z ϭ 239 [M ϩ H]ϩ, 183, 124, 93 (100), 57.
C12H17NO2S: calcd. C 60.22, H 7.16, N 5.85; found C 60.13, H
7.25, N 5.95.
3033, 2954, 1740, 1684, 1606, 1525, 1456, 1190 cmϪ1 1H NMR
.
(CDCl3, 200 MHz, 25 °C): δ ϭ 3.55 (s, 2 H), 3.67 (s, 4 H), 3.96 (d,
J ϭ 5.6 Hz, 2 H), 5.01 (t, J ϭ 4.9 Hz, 1 H), 5.15 (s, 4 H), 5.16 (s,
2 H), 6.58 (d, J ϭ 8.1 Hz, 1 H), 6.78 (t, J ϭ 7.6 Hz, 1 H), 7.08 (t,
J ϭ 7.8 Hz, 1 H), 7.31 (s, 2 H), 7.33 (s, 3 H), 7.42 (d, J ϭ 7.9 Hz,
1 H), 9.51 (br. s, 1 H) ppm. 13C NMR (CDCl3, 50 MHz, 25 °C):
δ ϭ 46.3, 56.5(2), 59.6, 66.9, 67.1(2), 112.5, 118.6, 124.2, 125.0,
126.8, 128.6(15), 135.3(2), 135.6, 140.8, 169.5, 171.1, 171.2(2) ppm.
MS: m/z ϭ 610 [M ϩ H]ϩ, 592, 502, 435, 364, 236, 91 (100). HRMS
(ESI): calcd. for C35H35N3O7Na [M ϩ Na]ϩ m/z ϭ 632.23727,
found 632.2370.
4H-1,4-Benzothiazin-3-one (18): White solid. M.p. 176Ϫ178 °C. IR
(KBr): ν˜ ϭ 3197, 3063, 1662, 1593, 1479, 1386, 740 cmϪ1. 1H NMR
(CDCl3, 200 MHz, 25 °C): δ ϭ 3.45 (s, 2 H), 6.93 (dd, J ϭ 1.4,
7.9 Hz, 1 H), 7.04 (td, J ϭ 1.4, 7.6 Hz, 1 H), 7.18 (td, J ϭ 1.5,
7.8 Hz, 1 H), 7.32 (d, J ϭ 7.8 Hz, 1 H), 9.43 (s, 1 H) ppm. 13C
NMR (CDCl3, 50 MHz, 25 °C): δ ϭ 28.9, 117.2, 119.0, 122.9,
126.9, 127.3, 137.4, 165.2 ppm. MS: m/z ϭ 165 [M]ϩ (100), 136,
120, 96. HRMS (ESI): m/z calcd. for C8H7NNaOS [M ϩ Na]ϩ
188.0147, found 188.0151.
N-[N-o-(Carboxymethylamino)phenylcarbamoylmethyl]imino-
diacetic Acid (2): A mixture of 15 (0.126 g, 0.2 mmol), MeOH
(12 mL), and 20% palladium hydroxide on charcoal (Pearlman’s
catalyst; 19 mg, 0.03 mmol) was stirred under hydrogen gas (1 atm)
for 1.5 h at room temperature. The catalyst was filtered off and the
4-(tert-Butoxycarbonylmethyl)-4H-1,4-benzothiazin-3-one
(19):
Colourless oil. IR (KBr): ν˜ ϭ 2978, 1743, 1679, 1586, 1480, 1367,
filtrate concentrated to dryness to afford a white amorphous solid 1154, 752 cmϪ1. H NMR (CDCl3, 200 MHz, 25 °C): δ ϭ 1.47 (s,
1
(0.068 mg, 0.20 mmol, 100%). M.p. 178Ϫ180 °C. IR (KBr): ν˜ ϭ 9 H), 3.45 (s, 2 H), 4.58 (s, 2 H), 6.87 (dd, J ϭ 1.2, 8.1 Hz, 1 H),
3436, 1746, 1664, 1612, 1513, 1355, 1242 cmϪ1. 1H NMR (CD3OD,
7.03 (td, J ϭ 1.1, 7.5 Hz, 1 H), 7.23 (td, J ϭ 1.5, 7.8 Hz, 1 H), 7.38
(dd, J ϭ 1.5, 7.6 Hz, 1 H) ppm. 13C NMR (CDCl3, 50 MHz, 25
200 MHz, 25 °C): δ ϭ 3.66 (s, 2 H), 3.69 (s, 4 H), 3.93 (s, 2 H),
6.62 (d, J ϭ 7.8 Hz, 1 H), 6.71 (t, J ϭ 7.7 Hz, 1 H), 7.12 (t, J ϭ °C): δ ϭ 28.1(3), 31.3, 47.8, 82.6, 117.3, 123.8, 127.5, 128.5, 139.7,
7.7 Hz, 1 H), 7.25 (d, J ϭ 7.8 Hz, 1 H) ppm. 13C NMR (CD3OD, 165.8, 167.6 ppm. MS: m/z ϭ 297 [M ϩ NH4]ϩ, 280, 241 (100),
50 MHz, 25 °C): δ ϭ 46.2, 57.6(2), 59.7, 112.8, 118.5, 124.0, 127.7,
128.8, 143.9, 172.6, 174.5(2), 175.2 ppm. MS (ES): m/z ϭ 338 [M
224. HRMS (ESI): calcd. for C14H17NNaO3S [M ϩ Na]ϩ m/z ϭ
302.0827, found 302.0830.
Eur. J. Org. Chem. 2004, 878Ϫ885
www.eurjoc.org
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
883

S. G. Gouin, E. Benoist, J.-F. Gestin, J. C. Meslin, D. Deniaud
FULL PAPER
N-[o-(tert-Butoxycarbonylmethylsulfanyl)phenyl]-2-benzyloxy-
carbonylaminoethanamide (20): Oxalyl chloride (601 µL, 888 mg,
7 mmol) and dimethylformamide (40 µL, 38 mg, 0.52 mmol) were
added under nitrogen at 0 °C to a suspension of N-(benzyloxycar-
7.0 Hz, 1 H), 10.46 (s, 1 H) ppm. 13C NMR (CDCl3, 50 MHz, 25
°C): δ ϭ 28.8(3), 39.2, 45.9, 82.1, 120.2, 122.0, 124.0, 130.2, 135.7,
139.6, 168.7, 171.3 ppm. MS: m/z ϭ 314 [M ϩ NH4]ϩ, 297(100),
241, 84. HRMS (ESI): calcd. for C14H20N2NaO3S [M ϩ Na]ϩ
bonyl)glycine (1.37 g, 6.54 mmol) in anhydrous CH2Cl2 (20 mL). m/z ϭ 319.10923, found 319.1092.
The ice-water bath was removed and stirring was continued at am-
bient temperature for 2 h. The mixture was added to a solution
Di-tert-butyl N-[N-o-(tert-Butoxycarbonylmethylsulfanyl)phenyl-
carbamoylmethyl]iminodiacetate (23): mixture of 21 (0.4 g,
of 17 (0.6 g, 2.5 mmol) and Et3N (2.86 mL, 20 mmol) in CH2Cl2
(20 mL). After being stirred at room temperature for 18 h, the sol-
vent was evaporated in vacuo. The resulting residue was partitioned
between CH2Cl2 (60 mL) and water (2 ϫ 40 mL). The organic ex-
tract was dried (MgSO4) and filtered and then the solvents were
evaporated. The residual oil was crystallised by trituration with
Et2O to give 20 as a white solid that was dried under vacuum
(0.734 g, 1.7 mmol, 68%). M.p. 73Ϫ75 °C. IR (KBr): ν˜ ϭ 3428,
3324, 2982, 2932, 2252, 1719, 1582, 1521, 1304, 1147, 910, 732
cmϪ1. 1H NMR (CDCl3, 200 MHz, 25 °C): δ ϭ 1.34 (s, 9 H), 3.35
(s, 2 H), 4.14 (d, J ϭ 5.8 Hz, 2 H), 5.18 (s, 2 H), 5.82 (br. s, 1 H),
7.05 (td, J ϭ 1.4, 7.6 Hz, 1 H), 7.36 (m, 7 H), 7.57 (dd, J ϭ 1.5,
7.8 Hz, 1 H), 8.35 (d, J ϭ 7.9 Hz, 1 H), 9.60 (s, 1 H) ppm. 13C
NMR (CDCl3, 50 MHz, 25 °C): δ ϭ 28.0(3), 40.4, 45.5, 67.3, 82.8,
120.7, 122.4, 124.6, 128.2, 128.6(2), 130.8, 136.4, 136.6, 139.9,
156.6, 167.4, 169.7 ppm. MS: m/z ϭ 448 [M ϩ NH4]ϩ, 431, 392,
375(100). HRMS (ESI): calcd. for C22H26N2NaO5S [M ϩ Na]ϩ
m/z ϭ 453.1460, found 453.1465.
A
0.77 mmol) and piperidine (4 mL, 4 mmol) in freshly distilled
CH2Cl2 (20 mL) was stirred under a hydrogen atmosphere for
20 min and then concentrated in vacuo. The crude product was
dissolved in anhydrous THF (10 mL) and then potassium carbon-
ate (1.07 g, 7.74 mmol), potassium iodide (0.025 g, 0.15 mmol), and
tert-butyl bromoacetate (1.443 mL, 1.93 g, 9.9 mmol) were added.
The resulting solution was heated at 70 °C for 5 h. After cooling
to room temperature, the mixture was concentrated to dryness. The
resulting residue was partitioned between CH2Cl2 (30 mL) and
water (20 mL). The organic extract was dried (MgSO4) and filtered
and then the solvents were evaporated. The residue was purified by
flash chromatography on silica gel (CH2Cl2/EtOAc, 96:4) to give
23 as a colourless oil (0.302 g, 0.58 mmol, 75%). IR (KBr): ν˜ ϭ
1
3055, 2984, 1731, 1686, 1518, 1266, 739 cmϪ1. H NMR (CDCl3,
200 MHz, 25 °C): δ ϭ 1.36 (s, 9 H), 1.45 (s, 18 H), 3.43 (s, 2 H),
3.55 (s, 2 H), 3.58 (s, 2 H), 7.05 (td, J ϭ 1.4, 7.5 Hz, 1 H), 7.35 (t,
J ϭ 7.6 Hz, 1 H), 7.58 (dd, J ϭ 1.4, 7.8 Hz, 1 H), 8.40 (d, J ϭ
8.2 Hz, 1 H), 10.43 (br. s, 1 H) ppm. 13C NMR (CDCl3, 100 MHz,
25 °C): δ ϭ 27.8(3), 28.2(6), 38.8, 56.5(2), 59.1, 81.7(2), 81.8, 120.8,
122.9, 124.1, 130.0, 135.6, 139.4, 168.6, 169.5, 169.8 ppm. MS:
m/z ϭ 525 [M ϩ H]ϩ (100), 216, 150. HRMS (LSIMS): calcd. for
C26H40N2O7S [M]ϩ m/z ϭ 524.25562, found 524.2560.
2-(9-Fluorenylmethoxycarbonyl)amino-N-[o-(tert-butoxy-
carbonylmethylsulfanyl)phenyl]ethanamide (21): Oxalyl chloride
(100 µL, 148 mg, 1.16 mmol) and dimethylformamide (10 µL,
9.5 mg, 0.13 mmol) were added under nitrogen at 0 °C to a suspen-
sion of N-(9-fluorenylmethoxycarbonyl)glycine (0.3 g, 1.01 mmol)
in anhydrous THF (5 mL). The ice-water bath was removed and
stirring was continued at ambient temperature for 30 min. The mix-
ture was added to a solution of 17 (0.2 g, 0.84 mmol) and diisopro-
pylethylamine (541 µL, 3.16 mmol) in THF (5 mL). After being
stirred at room temperature for 1 h, the solvent was evaporated in
vacuo. The resulting residue was partitioned between CH2Cl2
(20 mL) and water (2 ϫ 20 mL). The organic extract was dried
(MgSO4) and filtered and then the solvents were evaporated. The
residue was purified by flash chromatography on silica gel (CH2Cl2
then CH2Cl2/EtOAc, 5:95) to give 21 as a white solid (0.404 g,
0.78 mmol, 93%). M.p. 37Ϫ39 °C. IR (KBr): ν˜ ϭ 3054, 1723, 1507,
N-[N-o-(Carboxymethylsulfanyl)phenylcarbamoylmethyl]imino-
diacetic Acid Trifluoroacetate Salt (3): Compound 23 (0.129 g,
0.25 mmol) was stirred for 5 h at room temperature in trifluoro-
acetic acid (1 mL) and then concentrated in vacuo. The crude prod-
uct was dissolved again in trifluoroacetic acid (1 mL) and was
stirred at room temperature for 20 h. This protocol was repeated
twice. The solution was concentrated to dryness to afford a white
amorphous solid (0.117 g, 0.25 mmol, 100%). M.p. 52Ϫ54 °C. IR
(KBr): ν˜ ϭ 3434, 3016, 1730, 1696, 1582, 1539, 1440, 1260, 1193
1
cmϪ1. H NMR (CF3CO2D, 400 MHz, 25 °C): δ ϭ 3.77 (s, 2 H),
4.74 (s, 4 H), 4.91 (s, 2 H), 7.40Ϫ7.70 (m, 4 H) ppm. 13C NMR
(CD3OD, 100 MHz, 25 °C): δ ϭ 38.8, 56.4(2), 59.5, 123.3, 126.4,
126.6, 130.5, 136.0, 139.8, 171.1, 173.1, 173.4(2) ppm. MS
(LSIMSϩ): m/z ϭ 357.1 [M ϩ H]ϩ, 378.9 [M ϩ Na]ϩ, 395 [M ϩ
K]ϩ. MS (LSIMSϪ): m/z ϭ 355.1 [M Ϫ H]ϩ (100), 377.0 [M ϩ
Na Ϫ H]. C16H17F3N2O9S: calcd. C 40.85, H 3.64, N 5.96; found
C 40.82, H 3.91, N 6.17.
1437, 1265, 739 cmϪ1 1H NMR (CDCl3, 200 MHz, 25 °C): δ ϭ
.
1.34 (s, 9 H), 3.38 (s, 2 H), 4.23 (m, 2 H), 4.44 (s, 1 H), 4.48 (s, 1
H), 5.86 (br. s, 1 H), 7.07 (td, J ϭ 1.2, 7.6 Hz, 1 H), 7.31Ϫ7.67 (m,
9 H), 7.77 (d, J ϭ 7.0 Hz, 1 H), 8.39 (d, J ϭ 8.1 Hz, 1 H), 9.68 (s,
1 H) ppm. 13C NMR (CDCl3, 50 MHz, 25 °C): δ ϭ 28.0(3), 40.6,
45.5, 47.2, 67.5, 82.9, 120.1, 120.7, 122.3, 124.6, 125.2, 127.2, 127.8,
130.9, 136.7, 139.9, 141.4, 143.9, 156.6, 167.5, 169.9 ppm. MS:
m/z ϭ 537 [M ϩ NH4]ϩ, 519, 297, 214 (100), 179. HRMS (ESI):
calcd. for C29H30N2NaO5S [M ϩ Na]ϩ m/z ϭ 541.17731, found
541.17730.
Complexation Studies with 111In: Stock solutions of each chelate
(2500, 250, 25, and 2.5 nmol·mLϪ1) were prepared in 0.1  sodium
acetate (pH 5.7). To form the 111In-chelated complexes, a radioac-
tive solution of 111InCl3 (10 mCi·mLϪ1; 10 µL, 0.62 pmol) and a
2-Amino-N-[o-(tert-butoxycarbonylmethylsulfanyl)phenyl]ethan-
amide (22): Compound 21 (0.456 g, 0.88 mmol) was dissolved in solution of InCl3 (48 pmol·µLϪ1 in 0.05  hydrochloric acid; 4.2
CH2Cl2 (20 mL) and treated with piperidine (4 mL, 4 mmol). The
reaction mixture was stirred for 20 min under a nitrogen atmos-
phere and then concentrated in vacuo to afford a solid. The residue
was purified by column chromatography on silica gel (CH2Cl2/
µL, 200 pmol) was added to each chelating agent 1, 2, or 3 (1 or
10 equiv) or 1 and 3 (1000 equivalents), before adjustment of the
volume (to 150 µL). The nonradioactive solution of InCl3 was used
to maintain a fixed concentration of indium during the experiment.
EtOAc/Et3N, 83:15:2) to give amine 22 as a colourless oil (0.203 g, The final pH of each solution ranged from 5.6 to 5.8, with a final
0.68 mmol, 78%). IR (KBr): ν˜ ϭ 3255, 2979, 1724, 1684, 1518,
111In concentration of 48 nmol·mLϪ1. After incubation at 37 °C
1297, 1132, 736 cmϪ1 1H NMR (CDCl3, 200 MHz, 25 °C): δ ϭ for 1 h and thin-layer chromatography on cellulose plates (Merck
1.33 (s, 9 H), 3.43 (s, 2 H), 3.57 (s, 2 H), 7.05 (td, J ϭ 1.4, 7.5 Hz, 5552/0025; elution with 0.1  sodium acetate, pH 5.7), com-
1 H), 7.34 (m, 1 H), 7.58 (dd, J ϭ 1.6, 7.8 Hz, 1 H), 8.47 (d, J ϭ plexation was measured using a 445SI phosphoimager.
.
884
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2004, 878Ϫ885

New Analogues of Polyaminocarboxylic Acids
FULL PAPER
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Acknowledgments
The authors are grateful to the French Ministry of Education, the
CNRS, and the Ligue Nationale Contre le Cancer for financial sup-
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