Mixed catechol-hydroxamate and catechol-(o-hydroxy)phenacyl siderophores: synthesis and uptake studies with receptor-deficient Escherichia coli mutants

Article abstract of DOI:10.1016/j.tet.2007.12.004

Biscatechol-hydroxamate and catechol-bishydroxamate chelators of similar architecture were synthesized by a small set of acylation reactions, Michael additions, and domino Wittig alkenations and they were tested for siderophoric activity in various recept

Full text of DOI:10.1016/j.tet.2007.12.004

Available online at www.sciencedirect.com
Tetrahedron 64 (2008) 1711e1720
www.elsevier.com/locate/tet
Mixed catechol-hydroxamate and catechol-(o-hydroxy)phenacyl
siderophores: synthesis and uptake studies with receptor-deficient
Escherichia coli mutants
*
Rainer Schobert , Andreas Stangl, Kerstin Hannemann
Organisch-chemisches Laboratorium der Universita¨t, 95440 Bayreuth, Germany
Received 8 October 2007; received in revised form 29 November 2007; accepted 4 December 2007
Available online 8 December 2007
Abstract
Biscatechol-hydroxamate and catechol-bishydroxamate chelators of similar architecture were synthesized by a small set of acylation reac-
tions, Michael additions, and domino Wittig alkenations and they were tested for siderophoric activity in various receptor-deficient mutants
of Escherichia coli under iron starvation. Growth promotion occurred only in mutants featuring catecholate recognizing receptors. Simplified
mimics of the natural siderophores parabactin and agrobactin, carrying an o-hydroxybenzamide instead of the 2-(o-hydroxyphenyl)oxazoline
ligand, were prepared analogously. Unlike the originals these mimics are fully functional siderophores in E. coli.
Ó 2007 Elsevier Ltd. All rights reserved.
Keywords: Siderophores; Receptor specificity; Wittig alkenation; Michael addition
1. Introduction
pathways, receptor specificities, and essential structural fea-
tures as well as a short reliable synthetic strategy.
Most bacteria under aerobic conditions excrete specific
chelators, so-called siderophores, to sequester and transport
Fe(III), which is essential for them.1e5 Bacterial siderophores
feature tris-bidentate ligands of the catechol, hydroxamate, or
carboxylate types aptly positioned for octahedral coordination
of the metal. Cognate outer membrane receptors then recog-
nize the resulting siderophoreeiron complexes and initiate
their internalization.4,5 A few bacteria do not produce sidero-
phores of their own but rely entirely on alien ones, e.g., on
hydroxamates from fungi.6 Some competitors in the chemical
warfare of germs have adapted to this peculiarity by producing
conjugates of siderophores with antibiotic effectors (e.g., side-
romycins).2,7e9 Synthetic siderophores with various types and
combinations of ligands and with simplified structures were
also frequently employed as carriers for antibiotics.3,7,10e12
Their rational design requires information on the uptake
In a preceding paper13 we reported on such a short synthe-
sis of triscatechol and biscatechol-hydroxamate siderophores.
Herein we extend this methodology to the synthesis of other
mixed-ligand siderophores with hydroxamate, catechol, and
(o-hydroxy)phenacyl groups and we also elucidate their up-
take pathways in growth promotion experiments with recep-
tor-deficient mutants of Escherichia coli.
2. Results and discussion
2.1. Synthesis of mixed catechol-hydroxamate chelators
A series of tris-bidentate chelators with different combina-
tions of catechol, hydroxamate, and (o-hydroxy)phenacyl
ligands were prepared for receptor specificity and siderophoric
activity studies. They are all capable of strain-free octahedral
coordination of Fe(III) cations as to MM2 force field calcula-
tions. The biscatechol-hydroxamate 7 was available from benz-
yl acrylate 1 in five steps (Scheme 1; top). Michael addition
* Corresponding author. Fax: þ49 (0)921 552671.
E-mail address: rainer.schobert@uni-bayreuth.de (R. Schobert).
0040-4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.12.004

1712
R. Schobert et al. / Tetrahedron 64 (2008) 1711e1720
CHO
HN
O
O
+ 2
4
HO
O
BnO
+ 2 Ph3PCCO (5)
OBn
N
O
OBn
CO2Bn
HN
O
N
O
(i),(ii)
(iii)
N
N(OBn)
O
(iv)
BnO2C
RO
OR
N(OR)
CO2R
CO2Bn
2
HO
1
2
3
6: R = Bn, CH=CH
7: R = H, CH2–CH2
(v)
O
N
N[(CH2)2OH]2
H
N
H
N
O
X
RO
O
O
O
HN
(vii),(viii)
(ix)
(x)
BnO
BnO
BnO
BnO
BnO
N
H
O
N
H
O
O
HN
N
O
BnO
2
O
RO
OR
(v)
8: X = OH
9: X = NH(CH2)2
10
11
12: R = Bn
13: R = H
(vi)
NHBoc
Scheme 1. Reagents and conditions: (i) H2NOBn, EtOH, rt, 24 h, 63%; (ii) acryl chloride, NEt3, CH2Cl2, 0 ꢀC to rt, 30 min, 85%; (iii) [HO(CH2)2]2NH, EtOH, rt,
24 h, 60%; (iv) THF, cat. benzoic acid, rt, 8 h, 55%; (v) 5% Pd/C, H2 (1 bar), MeOH/dioxane, rt, 7 h, 95%; (vi) (a) SOCl2, H2N(CH2)2NHBoc, CH2Cl2, rt, 1.5 h,
100%, (b) NEt3, CH2Cl2, 0 ꢀC to rt, 30 min, 83%; (vii) 3 M HCl, THF, 0 ꢀC to rt, 2e3 h, then aq NaOH/CH2Cl2, 90%; (viii) acryl chloride, NEt3, CH2Cl2, 0 ꢀC to
rt, 30 min, 93%; (ix) [HO(CH2)2]2NH, EtOH, reflux, 48 h, 68%; (x) AcN(OBn)(CH2)2CO2H and ClCO2Et premixed, CH2Cl2, NEt3, 0 ꢀC, 30 min, then added to
11, CH2Cl2, 0 ꢀC to rt, 5 h, 56%.
of benzoxamine afforded benzyl 3-(N-benzoxamino)propio-
nate, which was immediately acylated with acryl chloride to
give benzoxamate 2. A further Michael addition of diethanol-
amine yielded the diol 3, which was bis-esterified in a three-
component domino reaction with aldehyde 413 and ylide 514 to
give 6. In this domino process15 the hydroxy groups of 3 added
across the C]C bond of ylide 5 to form a stabilized bisester
ylide, which in turn Wittig-alkenated the aldehyde group of 4.
Subsequent catalytic hydrogenation left chelator 7 as a colorless
foamy solid. A catechol-bishydroxamate 13 was also built up on
a route based upon acylation and Michael addition reactions
starting from dibenzoxybenzoic acid 816 (Scheme 1; bottom).
This was coupled with mono-Boc-protected ethylenediamine
to give compound 9. Cleavage of the Boc group followed by
acylation with acryl chloride afforded acryl amide 10, which
was treated with diethanolamine. The resulting diol 11 was bis-
acylated with 3-[N-(benzoxy)acetamido]propionic acid17 via
mixed-anhydride coupling furnishing the benzyl protected
precursor 12. Hydrogenolysis produced the colorless solid che-
lator 13.
A third type of catechol chelator in which an oxazoline het-
eroatom in a formal benzyl position can take part in ligating is
found in parabactin (14a) and agrobactin (14b), as produced
by Paracoccus denitrificans and Agrobacterium tumefaciens,
respectively.18 The natural enantiomers of 14 are derived
from L-threonine and form L-configured19a Fe(III) complexes,
which are not recognized by the receptors of E. coli.19b We
now prepared achiral analogs with longer spacers between
the phenyl rings and with either an imidazoline (e.g., 15) or
a salicylamide (e.g., 16) as a potential donor group (Fig. 1).
They were tested for siderophoric activity in an E. coli mutant
strain devoid of own siderophores.
The synthesis of the imidazolines 15 started from the 2-
(o-benzoxy)phenylimidazolines 18, which were readily acces-
sible by oxidative cyclization of (di)benzoxybenzaldehyde
17a20 or 17b,21 respectively, with ethylenediamine and N-bro-
mosuccinimide (NBS)22 (Scheme 2; top). N-acylation of 18
with acryl chloride gave the corresponding acryl amides 19,
which were in turn reacted with diethanolamine to furnish
the diols 20. These were submitted to the three-component re-
action with ylide 5 and aldehyde 4 as described above afford-
ing the pre-chelators 21. Their hydrogenation eventually left
the ligands 15 as pale yellow solids. The route to chelators
16 was based on a two-fold three-component reaction with
ylide 5. The first one with aldehyde 4 and N-Boc-diethanol-
amine 2223 afforded the biscatechol fragment 23a. Cleavage
of its Boc group liberated amine 23b, which was submitted
X
OH
R
HO
HO
(CH2)n
N
O
H
O
N
OH
O
O
N
HO
O
O
H
H
N
N
N
O
OH
O
O
OH
O
OH
15: n = 2;
16: n = 3;
OH
X
X
N
H
R =
O
C
R =
OH
OH
14a (Parabactin): X = H
14b (Agrobactin): X = OH
N
N
O
NH
Figure 1. Triscatechol and biscatechol-(o-hydroxy)phenacyl chelators: the nat-
ural siderophores parabactin (14a) and agrobactin (14b), and synthetical
mimics 15 and 16.

R. Schobert et al. / Tetrahedron 64 (2008) 1711e1720
1713
R1
N
NR2
OBn
N
N
N[(CH2)2OH]2
(iv)
OR2
N
CHO
O
OBn
R1
OBn
OR2
(i)
(iii)
R2O
O
N
R1
R
O
H
N
N
O
2
O
21a: R1 = H, R2 = Bn, CH=CH
21b: R1 = OBn, R2 = Bn, CH=CH
15a: R1 = R2 = H, CH2–CH2
17a: R1 = H
18a: R1 = R2 = H
18b: R1 = OBn, R2 = H
20a: R = H
20b: R = OBn
17b: R1 = OBn
(v)
(ii)
19a: R1 = H, R2 = C(O)CH=CH2
15b: R1 = OH, R2 = H, CH2–CH2
19b: R1 = OBn, R2 = C(O)CH=CH2
CHO
HN
O
+
O
OR2
N
O
R1
BnO
R1
OR2
24/4: R1 = H / OBn
HN
Boc
N
+ 4 (2 eq)
+ 5 (2 eq)
O
R2O
+ 5
RHN
NH
O
H
(vi)
(vi)
N
O
O
HO
OH
2
O
BnO
OBn
O
2
23a: R = Boc
23b: R = H
25a: R1 = H, R2 = Bn, CH=CH
25b: R1 = OBn, R2 = Bn, CH=CH
16a: R1 = R2 = H, CH2–CH2
22
(vii)
(viii)
16b: R1 = OH, R2 = H, CH2–CH2
Scheme 2. Reagents and conditions: (i) (a) H2N(CH2)2NH2, CH2Cl2, 0 ꢀC, 20 min, (b) NBS, 0 ꢀC to rt, 16 h, c) satd aq NaHCO3, 90/88% (a/b); (ii) acryl chloride,
NEt3, CH2Cl2, 0 ꢀC to rt, 30 min, 68/63% (a/b); (iii) [HO(CH2)2]2NH, EtOH, rt, 24 h, 65/54% (a/b); (iv) 5 (2 equiv), 4 (2 equiv), THF, cat. benzoic acid, rt, 8 h, 60/
55% (a/b); (v) 10% Pd/C, H2 (1 bar), MeOH/dioxane, rt, 36 h, 95%; (vi) THF, cat. benzoic acid, rt, 8 h, 58/66/58% (23a/25a/25b); (vii) 3 M HCl, THF, 0 ꢀC to rt,
2e3 h, then satd NaHCO3/CH2Cl2, 84%; (viii) 5% Pd/C, H2 (1 bar), MeOH/dioxane, rt, 16 h, 90/92% (16a/16b).
to the second three-component reaction with 5 and either alde-
hyde 4 or 24 to give the respective biscatechol-salicylamide
25a or triscatechol 25b. A concluding hydrogenolysis pro-
vided the potential siderophores 16.
hydroxamate and catechol siderophores.25 In strain H508525
the catecholate receptors of types Fep, Cir, and Fiu are defec-
tive or missing. Overnight cultures of these strains were plated
on agar, optionally containing the synthetic iron chelator
EDDA [ethylene diamine bis(o-hydroxyphenyl)acetic acid]
as a moderately effective iron sequestering agent to create
iron starvation conditions. Sterile cellulose filter discs imbued
with different concentrations of 7 or 13 were placed on the
dishes in sets of four and the diameters of the growth zones
resulting upon incubation at 36 ꢀC for 48 h were determined
and taken as a measure for siderophoric acivity.26 Table 1 sum-
marizes the results. In the presence of EDDA, compound 7
promoted the growth of E. coli mutants HK97 and H5596 in
a concentration-dependent manner (Fig. 2; left panel), while
virtually no growth was observed of the strain H5085. Similar
observations, albeit with less pronounced growth promotion,
2.2. Biological evaluation
2.2.1. Receptor specificity
The mixed-ligand chelators 7 and 13 were tested for side-
rophore properties on three E. coli mutants with defunct pro-
duction of species-own enterobactin and with defined
limitations of their receptor machinery. The strain HK97
(¼H5093) lacks receptors of types FhuA and FhuE, which rec-
ognize exogenous hydroxamate siderophores such as fungi-
produced ferrichromes and coprogens.24 The strain H5596,
like the wild type progenitor, owns receptors for both
Table 1
Growth influencing effects of chelators 7/13 on siderophore-deficient E. coli mutants
Amount applied (mg)
HK97a þEDDA
23/19
20/15
17/12
15/8
HK97 no EDDA
H5596b þEDDA
22/14
18/11
16/8
H5596 no EDDA
H5085c þEDDA
H5085 no EDDA
d
d
150
75
þþ /þþ
þþ/þþ
þþ/þþ
þþ/þþ
þþ/þþ
ꢁ ꢁ /ꢁ ꢁ
ꢁ23/þþ
ꢁ20/þþ
ꢁ17/þþ
ꢁ15/þþ
þþ/þþ
þþ/þþ
þþ/þþ
ꢁ ꢁ/ꢁ ꢁ
ꢁ ꢁ/ꢁ ꢁ
ꢁ ꢁ/ꢁ ꢁ
38
15
13/ꢁ ꢁ
Agar plates (MuellereHinton II medium, optionally 100 mg mLꢁ1 EDDA) inoculated with 100 mL of suspensions of the respective E. coli strains were covered
with 6 mm cellulose discs containing 15 mL of an ethanolic solution (10, 5, 2.5, or 1 mg mLꢁ1) of 7 or 13, respectively. The diameters (in mm) of the resulting
growth (þ) or inhibition (ꢁ) zones were determined after 48 h of incubation at 36 ꢀC and are cited here.
a
HK97 (¼H5093): defective hydroxamate receptors due to FhuAꢁ and FhuEꢁ.
b
H5596: hydroxamate and catecholate receptors like wild type.
H5085: defective catecholate receptors FepA, Cir, and Fiu.
c
d
þþ: confluent growth all over the plate; ꢁ ꢁ: no growth at all.

1714
R. Schobert et al. / Tetrahedron 64 (2008) 1711e1720
Figure 2. Effects of chelator 7 in E. coli strains HK97 featuring catecholate-specific receptors (left panel) and H5085 lacking such receptors (right panel). Con-
ditions as stated in Table 1. Pictures were taken after 48 h of incubation at 36 ꢀC.
were made for ligand 13. This suggests that Fe(III) complexes
of both chelators 7 and 13 were actively internalized only via
the catecholate rather than the hydroxamate receptors. In the
absence of EDDA, bacteria of strains HK97 and H5596
grew fast and eventually spread all over the dishes, with and
without compounds 7 and 13 being present. Strain H5085
grew slowly in the absence of EDDA and only beyond a dis-
tinct growth inhibition zone around the cellulose discs impreg-
nated with 7 (Fig. 2; right panel). Formation of chelate
complexes not recognized by the receptors of H5085 appar-
ently led to iron depletion in the diffusion zone of 7, while
further afield growth was entertained by passive receptor-inde-
pendent iron uptake. Interestingly, this inhibitory effect on
H5085 was not observed for compound 13. In brief, chelators
7 and, to a lower extend, 13 are reasonably good siderophores,
both binding ferric ions more strongly than EDDA and both
being recognized and internalized exclusively by receptors
specific for catecholates.
triscatechol chelators (b) were more strongly growth promot-
ing than their biscatechol-(monohydroxy)phenyl analogs (a)
and the hydroxybenzamides 16 exhibited a stronger sidero-
phoric effect than the imidazolines 15. Chelator 16b was
even as efficacious as the natural siderophore ferrichrome.
Apparently, the formation of five-membered chelate rings is
favored over that of six-membered ones and that of O,O-
chelates over that of O,N-chelates. Hence compounds 15b
and 16b act as genuine triscatechol ligands. Support for this
rationale comes from the observation that the replacement of
the benzamide in compound 16a by a benzoate group results
in a complete loss of activity as esters are less good O-donor
ligands than amides. The 1:1 stoichiometry of Fe(III) com-
plexes of chelators 16a and also of 7 (as part of a conjugate
with the antibiotic lorabid) was proved spectrophotometrically
by measuring at lmax (510 nm) of their visible absorption band
according to a method by Bergeron.27
3. Conclusions
2.2.2. Siderophoric activity of chelators 15 and 16
E. coli H5596 bacteria, featuring both catecholate and
hydroxamate receptors but lacking own siderophores, were
treated in agar diffusion tests under iron starvation with the
mimics of parabactin (15a, 16a) and of agrobactin (15b,
16b). Table 2 summarizes the results. In general, the
We have established short synthetic routes to different tris-
catechol, biscatechol-hydroxamate, and catechol-bishydroxa-
mate chelators based upon a small set of reliable acylation
reactions, Michael additions, and domino Wittig alkenations.
The finding that mixed catechol-hydroxamate siderophores
are internalized exclusively by catecholate-specific receptors
of E. coli renders conceivable drug conjugates of them attrac-
tive as antibiotic tools for the selection of mutants with limited
receptor machineries. The methodology for the conjugation of
these siderophores to b-lactam antibiotics under non-aqueous
conditions is in place.13 However, preliminary studies of a lor-
acarbef conjugate revealed an only mediocre antibacterial
activity in E. coli and Bacillus subtilis despite a high uptake.
This might be due to an incomplete intracellular breakdown
of the drugesiderophore conjugate. Further work is in prog-
ress here. Finally, we prepared simplified mimics of the natu-
ral siderophores parabactin and agrobactin which, unlike the
originals, are fully functional in E. coli. The high activity of
16a means that a catechol ligand as part of an octahedral co-
ordination sphere can be replaced by a salicylamide group.
Table 2
Promotion of growth of siderophore-deficient E. coli mutant H5596 under iron
limitation by chelators 15 and 16
Amount applied (mg)
15a
15b
16a
16b
150
75
9 [0.20]a
0 [0.10]
0 [0.05]
0 [0.02]
16 [0.19]
14 [0.10]
12 [0.05]
9 [0.02]
17 [0.23]
15 [0.12]
12 [0.06]
9 [0.02]
24 [0.22]
21 [0.11]
20 [0.06]
16 [0.02]
38
15b
Agar plates (MuellereHinton II medium, 100 mg mLꢁ1 EDDA) inoculated
with 100 mL of an E. coli H5596 suspension were covered with 6 mm cellulose
discs containing 15 mL of an ethanolic solution (10, 5, 2.5, or 1 mg mLꢁ1) of
the respective compound. The diameters (in mm) of the resulting growth zones
were determined after 48 h of incubation at 36 ꢀC and are cited here.
a
The applied quantities in mmol for each compound are given in brackets.
In a reference run 15 mg of natural trishydroxamate siderophore ferri-
chrome were applied causing a growth zone of 17 mm diameter.
b

R. Schobert et al. / Tetrahedron 64 (2008) 1711e1720
1715
4. Experimental
4.2.2. N-Benzyloxy-N-benzoxycarbonylethyl 3-bis(20-
hydroxyethyl)aminopropionamide 3dtypical procedure for
the Michael addition of amines
4.1. General
A solution of diethanolamine (0.63 g, 6.0 mmol) and acryl
amide 2 (1.70 g, 5.0 mmol) in ethanol (20 mL) was stirred at
room temperature for 24 h. The solvent was evaporated and
the residue filtered through a short plug of silica gel 60 with
ethyl acetate/methanol (10:1) and then dried on an oil pump
to give 3 (1.33 g, 60%); pale yellow, highly viscous oil;
nmax/cmꢁ1 3424, 2948, 1735, 1658, 1455; dH (300 MHz,
CDCl3) 2.40e2.55 (6H, m), 2.58 (2H, t, J¼6.6 Hz), 2.72
(2H, t, J¼6.1 Hz), 3.46 (2H, br s), 3.53 (4H, t, J¼5.1 Hz),
3.94 (2H, t, J¼6.6 Hz), 4.77 (2H, s), 5.08 (2H, s), 7.20e
7.40 (10H, m); dC (75 MHz, CDCl3) 30.2, 31.9, 41.3, 48.6,
56.0, 59.3, 66.4, 76.1, 128.0, 128.1, 128.3, 128.5, 128.9,
129.2, 134.0, 135.4, 171.3, 174.4; m/z (EI, 70 eV, þMSTFA)
588 (Mþ, 2%), 499 (62%), 408 (11%), 262 (19%), 146
(14%), 130 (20%), 91 (100%). Anal. Calcd for C24H32N2O6:
C, 64.9; H, 7.3; N, 6.3. Found: C, 65.3; H, 7.1; N, 6.3%.
Melting points were determined with a Gallenkamp
apparatus and are uncorrected. IR-spectra were recorded
on a PerkineElmer One FTIR spectrophotometer. Nuclear
magnetic resonance (NMR) spectra were recorded under con-
ditions as indicated on a Bruker Avance 300 spectrometer.
Chemical shifts (d) are given in parts per million downfield
from TMS as internal standard. Mass spectra were recorded
using a Varian MAT 311A (EI). Elemental analyses were
carried out with a PerkineElmer 2400 CHN elemental ana-
lyzer. For column chromatography Merck silica gel 60
(230e400 mesh) was used. Solvents were dried and distilled
(THF, diethyl ether, and dioxane over Na/Ph2CO, CH3OH
over CaO, acetone over K2CO3, CH2Cl2, and CHCl3 over
P2O5) and stored under argon. Starting compounds were pur-
chased from the usual sources and were used without further
purification.
4.2.3. N-Benzyloxy-N-benzoxycarbonylethyl 3-di-[80-aza-30-
oxa-40,90-dioxo-90-(200,300-dibenzoxyphenyl)non-50-enyl]-
aminopropionamide 6dtypical procedure for the
4.2. Synthesis of biscatechol-hydroxamate chelator 7
4.2.1. N-Benzyloxy-N-benzoxycarbonylethyl acryl amide 2
A solution of benzyl acrylate 1 (1.62 g, 10.0 mmol) and
benzoxyamine (1.47 g, 12.0 mmol) in ethanol (30 mL) was
stirred at room temperature for 24 h. The solvent was evap-
orated and the residue was purified by column chromato-
graphy (silica gel 60, cyclohexane/ethyl acetate 2:1, Rf
0.58) to give 1.80 g (63%) benzyl 3-(benzoxyamino)propio-
nate as a colorless oil; nmax/cmꢁ1 3274, 3032, 2923, 1733,
1455; dH (300 MHz, CDCl3) 2.66 (2H, t, J¼6.3 Hz), 3.24
(2H, t, J¼6.3 Hz), 4.70 (2H, s), 5.14 (2H, s), 5.84 (1H, br
s), 7.25e7.45 (10H, m); dC (75 MHz, CDCl3) 32.4, 47.5,
66.3, 76.7, 127.8, 128.0, 128.3, 128.4, 128.6, 128.9, 135.9,
137.8, 172.4; m/z (EI, 70 eV) 285 (Mþ, 4%), 194 (7%),
181 (52%), 91 (100%). Anal. Calcd for C17H19NO3: C,
71.6; H, 6.7; N, 4.9. Found: C, 71.3; H, 6.9; N, 5.2%. A
solution of benzyl 3-(benzoxyamino)propionate (1.75 g,
6.1 mmol) and NEt3 (1.3 mL) in CH2Cl2 (30 mL) was slowly
treated at 0 ꢀC with a solution of acryl chloride (0.61 g,
6.7 mmol) in the same solvent (5 mL) by means of a syringe.
The mixture was stirred for 30 min and then washed with sat.
aq NaHCO3 and water. The organic phase was dried over
Na2SO4. Evaporation of the volatiles left a yellow oil that
upon column chromatography (silica gel 60, cyclohexane/
three-component domino Wittig alkenation with ylide 5
A solution of Ph3PCCO (5)14 (2.11 g, 6.98 mmol), alde-
hyde 413 (2.40 g, 6.40 mmol), diol 3 (1.29 g, 2.91 mmol),
and benzoic acid (85 mg, 0.70 mmol) in dry THF (100 mL)
was stirred at room temperature for 8 h. The solvent was re-
moved in vacuo and the residue was purified by column chro-
matography (silica gel 60, cyclohexane/ethyl acetate 1:2, Rf
0.38) to give 1.99 g (55%) of 6 as a pale yellow foam; nmax
/
cmꢁ1 3380, 3033, 2953, 1750, 1721, 1658, 1576, 1526; dH
(300 MHz, CDCl3) 2.48 (2H, t, J¼6.5 Hz), 2.62 (2H, t,
J¼7.1 Hz), 2.74 (4H, t, J¼6.2 Hz), 2.86 (2H, t, J¼6.5 Hz),
3.90e4.05 (6H, m), 4.14 (2H, t, J¼6.2 Hz), 4.78 (2H, s),
5.01 (2H, s), 5.13 (4H, s), 5.18 (4H, s), 5.82 (2H, dt,
J¼15.8, 1.7 Hz), 6.78 (2H, dt, J¼15.8, 5.1 Hz), 7.15e7.50
(34H, m), 7.65e7.75 (2H, m), 8.18 (2H, t, J¼6.7 Hz); dC
(75 MHz, CDCl3) 30.8, 32.1, 40.3, 50.2, 52.7, 62.6, 66.5,
71.4, 75.8, 76.4, 76.6, 117.3, 119.0, 121.6, 123.4, 124.2,
126.8, 127.3, 127.6, 127.7, 127.9, 128.0, 128.3, 128.5,
128.6, 128.7, 128.9, 129.1, 136.1, 136.4, 144.2, 146.9,
151.7, 164.5, 165.1, 165.8, 171.5. Anal. Calcd for
C74H74N4O14: C, 71.5; H, 6.0; N, 4.5. Found: C, 71.1; H,
6.3; N, 4.6%.
ethyl acetate 2:1, Rf 0.43) yielded 2 (1.76 g, 85%); nmax
/
4.2.4. N-Hydroxy-N-hydroxycarbonylethyl 3-di-[80-aza-30-
oxa-40,90-dioxo-90-(200,300-dihydroxyphenyl)nonyl]-
aminopropionamide 7dtypical procedure
for the hydrogenolytic debenzylation
Compound 6 (1.93 g, 1.55 mmol) was dissolved in freshly
distilled methanol/dioxane (1:1, 10 mL), 5% Pd on charcoal
(100 mg) was added and the resulting mixture was purged
with and kept under an atmosphere of hydrogen gas (1 bar)
for 7 h while stirring. After filtration, the solvent was removed
in vacuo. The residue was taken up in methanol (0.5 mL) and
re-precipitated by adding ethyl acetate. Upon storage in the
cmꢁ1 3033, 2949, 1732, 1660, 1454; dH (300 MHz, CDCl3)
2.68 (2H, t, J¼6.7 Hz), 4.02 (2H, t, J¼6.7 Hz), 4.80 (2H,
s), 5.09 (2H, s), 5.70 (1H, dd, J¼11.2, 2.0 Hz), 6.38 (1H,
dd, J¼17.1, 2.0 Hz), 6.67 (1H, dd, J¼11.2, 17.1 Hz),
7.20e7.40 (10H, m); dC (75 MHz, CDCl3) 32.1, 41.7, 66.5,
76.8, 126.1, 128.0, 128.2, 128.5, 128.6, 129.0, 129.3,
129.4, 134.0, 135.6, 166.9, 171.4; m/z (EI, 70 eV) 339
(Mþ, 1%), 232 (1%), 181 (24%), 91 (100%). Anal. Calcd
for C20H21NO4: C, 70.9; H, 6.2; N, 4.1. Found: C, 71.1;
H, 6.4; N, 4.0%.

1716
R. Schobert et al. / Tetrahedron 64 (2008) 1711e1720
refrigerator colorless compound 7 (1.03 g, 95%) was obtained;
mp 87e89 ꢀC; nmax/cmꢁ1 3315, 2976, 1739, 1684, 1635,
1470; dH (300 MHz, CD3OD) 1.80e1.95 (4H, m), 2.42 (4H,
t, J¼7.2 Hz), 2.57 (2H, t, J¼6.8 Hz), 2.78 (2H, t, J¼6.7 Hz),
3.05e3.20 (6H, m), 3.41 (4H, t, J¼6.6 Hz), 3.84 (2H, t,
J¼6.8 Hz), 4.22 (4H, t, J¼5.8 Hz), 6.69 (2H, t, J¼8.1 Hz),
6.93 (2H, dd, J¼8.1, 1.5 Hz), 7.21 (2H, dd, J¼8.1, 1.5 Hz);
dC (75 MHz, CD3OD) 25.7, 29.8, 32.4, 33.1, 39.8, 45.3,
52.1, 53.9, 62.0, 116.8, 118.7, 119.6, 119.7, 147.3, 150.4,
169.7, 171.7, 174.6, 176.1. Anal. Calcd for C32H42N4O14: C,
54.4; H, 6.0; N, 7.9. Found: C, 54.0; H, 6.1; N, 7.7%.
CDCl3) 41.0, 42.2, 72.8, 75.9, 116.6, 122.7, 124.0, 127.2,
127.3, 127.8, 128.2, 128.4, 136.0, 136.2, 146.4, 151.3,
165.1; m/z (EI, 70 eV) 376 (Mþ, 2%), 347 (20%), 334
(17%), 285 (28%), 227 (65%), 136 (50%), 91 (100%). It was
acylated with acryl chloride analogously to the synthesis of
2. Yield: 2.20 g (84%, with respect to 9); colorless solid of
mp 95 ꢀC; nmax/cmꢁ1 3376, 2970, 1655, 1571, 1533, 1458;
dH (300 MHz, CDCl3) 3.20e3.40 (4H, m), 5.07 (2H, s), 5.15
(2H, s), 5.62 (1H, dd, J¼10.1, 1.6 Hz), 5.91 (1H, dd,
J¼17.0, 10.1 Hz), 6.15 (1H, dd, J¼17.0, 1.6 Hz), 6.72 (1H,
br), 7.00e7.05 (2H, m), 7.25e7.45 (10H, m), 7.65e7.75
(1H, m), 8.20 (1H, d, J¼5.6 Hz); dC (75 MHz, CDCl3) 38.9,
41.2, 71.3, 76.5, 117.4, 123.0, 124.4, 125.7, 126.8, 127.6,
128.3, 128.7, 128.8, 128.9, 129.0, 131.1, 136.2, 136.3,
146.8, 151.6, 165.9, 166.9; m/z (EI, 70 eV) 430 (Mþ, 3%),
339 (9%), 225 (10%), 136 (8%), 91 (100%). Anal. Calcd for
C26H26N2O4: C, 72.5; H, 6.1; N, 6.5. Found: C, 72.3; H,
6.1; N, 6.2%.
4.3. Synthesis of catechol-bishydroxamate chelator 13
4.3.1. 20,30-Dibenzoxy-N-[2-(tert-butoxycarbonyl-
amino)ethyl]benzamide 9
A solution of dibenzoxybenzoic acid 816 (2.5 g, 7.5 mmol)
and thionyl chloride (3.6 g, 30.0 mmol) in CH2Cl2 (30 mL)
was stirred at room temperature for 1.5 h. All volatiles were
removed under reduced pressure and the oily residue was dried
on an oil pump to give 2,3-dibenzoxybenzoyl chloride as
a pale yellow waxy solid (2.6 g, 7.5 mmol). This was dissolved
in dry CH2Cl2 (10 mL) and added dropwise by means of a sy-
ringe to a stirred solution at 0 ꢀC of Boc-protected ethylenedi-
amine (1.44 g, 9.0 mmol) and NEt3 (1.2 mL) in the same
solvent (30 mL). The mixture was allowed to come to room
temperature and washed with satd aq NaHCO3. The organic
phase was dried (Na2SO4) and evaporated to leave a pale yel-
low solid, which was purified by column chromatography (sil-
ica gel 60, cyclohexane/ethyl acetate 1:3, Rf 0.58) yielding 9
(2.96 g, 83%) as a colorless solid of mp 108 ꢀC; nmax/cmꢁ1
3379, 2980, 1705, 1650, 1576, 1531; dH (300 MHz, CDCl3)
1.38 (9H, s), 3.05e3.15 (2H, m), 3.30e3.40 (2H, m), 4.82
(1H, br), 5.07 (2H, s), 5.14 (2H, s), 7.00e7.05 (2H, m),
7.25e7.45 (10H, m), 7.65e7.75 (1H, m), 8.02 (1H, t,
J¼6.1 Hz); dC (75 MHz, CDCl3) 28.3, 39.6, 41.0, 71.3, 76.4,
79.9, 117.1, 123.2, 124.4, 127.1, 127.7, 128.2, 128.6, 128.7,
128.8, 129.0, 136.2, 136.4, 146.7, 151.7, 156.1, 165.9; m/z
(EI, 70 eV) 476 (Mþ, 2%), 420 (11%), 329 (11%), 285
(24%), 91 (100%). Anal. Calcd for C28H32N2O5: C, 70.6; H,
6.8; N, 5.9. Found: C, 70.9; H, 6.9; N, 5.8%.
4.3.3. N-[2-(20,30-Dibenzoxybenzamido)ethyl]-300-bis(2000-hydr-
oxyethyl)aminopropionamide 11
Analogously to the synthesis of 3, compound 11 (1.78 g,
68%) was obtained as a colorless, highly viscous oil from
10 (2.10 g, 4.9 mmol) and diethanolamine (0.62 g,
5.9 mmol). Reflux conditions (48 h) were required for comple-
tion; nmax/cmꢁ1 3365, 2947, 1647, 1576, 1542, 1454; dH
(300 MHz, CDCl3) 2.23 (2H, t, J¼5.7 Hz), 2.55 (4H, t,
J¼5.2 Hz), 2.69 (2H, t, J¼5.7 Hz), 3.20e3.35 (4H, m), 3.54
(4H, t, J¼5.2 Hz), 3.99 (2H, br s), 5.05 (2H, s), 5.10 (2H,
s), 7.05e7.10 (2H, m), 7.25e7.45 (10H, m), 7.60e7.70 (1H,
m), 7.85 (1H, d, J¼5.2 Hz), 8.22 (1H, d, J¼5.6 Hz); dC
(75 MHz, CDCl3) 34.0, 39.2, 39.9, 51.1, 56.2, 59.5, 71.1,
75.3, 117.1, 122.6, 124.3, 126.9, 127.5, 128.2, 128.5, 128.6,
128.7, 128.9, 136.1, 136.2, 146.6, 151.6, 166.7, 173.1; m/z
(EI, 70 eV, þMSTFA) 678 (Mþꢁ1, 2%), 664 (6%), 576
(100%), 431 (9%), 262 (15%), 91 (47%). Anal. Calcd for
C30H37N3O6: C, 67.3; H, 7.0; N, 7.8. Found: C, 67.0; H,
7.1; N, 8.0%.
4.3.4. N-[2-(20,30-Dibenzoxybenzamido)ethyl]-300-
bis[2000-(30000-N-benzoxyacetamido)propanoyloxyethyl]-
aminopropionamide 12
4.3.2. 20,30-Dibenzoxy-N-[2-(acrylamino)ethyl]benzamide10
Compound 9 (2.90 g, 6.10 mmol) in THF (10 mL) was
treated at 0 ꢀC with 3 M HCl in THF (20 mL). The mixture
was stirred while slowly coming to room temperature. After
2e3 h, diethyl ether (100 mL) was added, and the precipitate
was filtered off and washed with diethyl ether. It was sus-
pended in CH2Cl2 (100 mL) and washed with cold diluted
aq NaOH (pH 10). The clear organic phase was separated
and dried over Na2SO4. Evaporation of all volatiles left
20,30-dibenzoxy-N-(2-aminoethyl)benzamide (2.06 g, 90%) as
a colorless oil, which was used as such; nmax/cmꢁ1 3370,
2963, 1654, 1576, 1533, 1454; dH (300 MHz, CDCl3) 1.45
(2H, br s), 2.55e2.65 (2H, m), 3.20e3.30 (2H, m), 5.02
(2H, s), 5.05 (2H, s), 7.00e7.05 (2H, m), 7.25e7.45 (10H,
m), 7.65e7.75 (1H, m), 8.02 (1H, t, J¼5.8 Hz); dC (75 MHz,
A stirred mixture of 3-[N-(benzoxy)acetamido]propionic
acid17 (0.90 g, 3.80 mmol), NEt3 (0.63 mL), and dry CH2Cl2
(15 mL) was treated at 0 ꢀC with chloroethyl formiate
(0.45 g, 4.20 mmol). After 30 min, the mixture was transferred
to an ice-cooled solution of diol 11 (0.92 g, 1.72 mmol) in the
same solvent (20 mL) by means of syringe. The mixture was
stirred at room temperature for 5 h and washed with satd aq
NaHCO3 and water. The organic phase was dried (Na2SO4)
and evaporated to leave a yellowish oil, which was purified
by column chromatography (silica gel 60, ethyl acetate/meth-
anol 4:1, Rf 0.33). Yield: 0.94 g (56%), colorless highly vis-
cous oil; nmax/cmꢁ1 3374, 2942, 1723, 1667, 1623, 1562,
1459; dH (300 MHz, CDCl3) 2.00 (3H, s), 2.02 (3H, s), 2.25
(2H, t, J¼6.2 Hz), 2.50e2.65 (6H, m), 2.70e2.80 (4H, m),
3.20e3.35 (4H, m), 3.55 (2H, t, J¼5.0 Hz), 3.86 (4H, t,

R. Schobert et al. / Tetrahedron 64 (2008) 1711e1720
1717
J¼6.6 Hz), 4.07 (2H, t, J¼5.6 Hz), 4.75 (2H, s), 4.77 (2H, s),
5.05 (2H, s), 5.10 (2H, s), 7.05e7.10 (2H, m), 7.25e7.45
(20H, m), 7.55e7.65 (1H, m), 7.73 (1H, d, J¼5.3 Hz), 8.20
(1H, d, J¼5.9 Hz); dC (75 MHz, CDCl3) 20.4, 31.8, 33.2,
38.9, 39.8, 41.2, 50.3, 51.7, 56.1, 58.7, 61.6, 71.1, 76.1,
76.3, 117.0, 122.7, 124.3, 126.9, 127.5, 128.1, 128.3, 128.5,
128.6, 128.7, 128.9, 129.2, 129.3, 134.0, 136.1, 136.2,
146.6, 151.6, 166.3, 171.2, 172.4, 174.5. Anal. Calcd for
C54H63N5O12: C, 66.8; H, 6.5; N, 7.1. Found: C, 66.9; H,
6.7; N, 7.0%.
5.12 (2H, s), 5.50 (1H, br s), 7.00e7.05 (2H, m), 7.30e7.50
(10H, m), 7.60e7.65 (1H, m); dC (75 MHz, CDCl3) 49.7,
71.1, 76.2, 115.9, 122.6, 124.4, 127.5, 128.1, 128.3, 128.5,
128.6, 128.8, 136.5, 136.8, 147.0, 151.9, 163.4; m/z (EI,
70 eV) 358 (Mþ, 5%), 267 (66%), 251 (21%), 239 (40%),
91 (100%). Anal. Calcd for C23H22N2O2: C, 77.1; H, 6.2; N,
7.8. Found: C, 77.4; H, 6.1; N, 7.6%.
4.4.3. 2-(20-Benzoxyphenyl)-1-propenoyl-4,5-dihydro-
imidazole 19a
Analogously to the synthesis of 2, compound 19a (2.06 g,
68%) was obtained from 18a (2.50 g, 9.9 mmol) and acryl
chloride (0.98 g, 10.9 mmol) as a pale yellow oil of Rf 0.48
4.3.5. N-[2-(20,30-Dihydroxybenzamido)ethyl]-300-
bis[2000-(30000-N-hydroxyacetamido)propanoyloxyethyl]-
aminopropionamide 13
(cyclohexane/ethyl acetate 1:2). Yield: 2.06 g (68%); nmax
/
cmꢁ1 3034, 2875, 2247, 1656, 1629, 1597, 1471; dH
(300 MHz, CDCl3) 3.90e4.05 (4H, m), 5.02 (2H, s), 5.41
(1H, dd, J¼10.6, 1.9 Hz), 5.92 (1H, dd, J¼16.7, 10.6 Hz),
6.23 (1H, dd, J¼16.7, 1.9 Hz), 6.90e6.95 (1H, m), 7.05e
7.10 (1H, m), 7.30e7.50 (7H, m); dC (75 MHz, CDCl3)
47.8, 53.0, 70.5, 112.5, 121.2, 122.3, 127.9, 128.4, 128.6,
128.8, 128.9, 129.8, 132.7, 136.5, 144.1, 156.6, 162.4; m/z
(EI, 70 eV) 306 (Mþ, 6%), 289 (9%), 251 (63%), 200
(94%), 132 (41%), 91 (100%). Anal. Calcd for C19H18N2O2:
C, 74.5; H, 5.9; N, 9.1. Found: C, 74.3; H, 5.9; N, 9.2%.
Analogously to the synthesis of 7, compound 13 (540 mg,
95%) was obtained from 12 (900 mg, 0.93 mmol) as a colorless
foamy solid of mp 86e88 ꢀC; nmax/cmꢁ1 3372, 2897, 1736,
1641, 1621, 1549, 1460; dH (300 MHz, CD3OD) 2.08 (6H, s),
2.58 (2H, t, J¼6.7 Hz), 2.69 (2H, t, J¼6.6 Hz), 2.78 (2H, t,
J¼6.1 Hz), 3.25e3.40 (4H, m), 3.45e3.60 (6H, m), 3.80e
3.95 (6H, m), 4.33 (2H, t, J¼5.3 Hz), 6.71 (1H, t, J¼7.9 Hz),
6.93 (1H, dd, J¼7.9, 1.1 Hz), 7.25 (1H, dd, J¼7.9, 1.1 Hz);
dC (75 MHz, CDCl3) 20.5, 29.2, 32.5, 39.9, 40.1, 44.9,
52.2, 53.5, 56.3, 56.4, 59.2, 116.5, 118.8, 119.6, 119.7,
147.0, 150.1, 169.9, 172.3, 172.8, 174.4. Anal. Calcd for
C26H39N5O12: C, 50.9; H, 6.4; N, 11.4. Found: C, 51.2; H,
6.2; N, 11.0%.
4.4.4. 2-(20,30-Dibenzoxyphenyl)-1-propenoyl-4,5-dihydro-
imidazole 19b
Analogously to 19a, compound 19b (1.74 g, 63%) was ob-
tained from 18b (2.40 g, 6.7 mmol) as a pale yellow viscous
oil of Rf 0.46 (cyclohexane/ethyl acetate 1:2); nmax/cmꢁ1
3032, 2875, 2247, 1656, 1630, 1595, 1473, 1412; dH
(300 MHz, CDCl3) 3.75e3.85 (4H, m), 5.06 (2H, s), 5.13
(2H, s), 5.36 (1H, dd, J¼10.4, 1.6 Hz), 5.83 (1H, dd,
J¼16.7, 10.4 Hz), 6.18 (1H, dd, J¼16.7, 1.6 Hz), 6.95e7.10
(3H, m), 7.20e7.45 (10H, m); dC (75 MHz, CDCl3) 47.3,
52.8, 70.9, 75.4, 116.6, 121.5, 124.4, 127.3, 127.6, 127.8,
127.9, 128.0, 128.2, 128.3, 128.4, 128.6, 136.4, 137.5,
146.6, 151.6, 156.1, 163.2; m/z (EI, 70 eV) 412 (Mþ, 4%),
357 (7%), 321 (38%), 267 (22%), 239 (13%), 215 (25%), 91
(100%). Anal. Calcd for C26H24N2O3: C, 75.7; H, 5.9; N,
6.8. Found: C, 75.9; H, 5.8; N, 6.9%.
4.4. Synthesis of the imidazoline chelators 15
4.4.1. 2-(20-Benzoxyphenyl)-4,5-dihydroimidazole 18a
A solution of 2-benzoxybenzaldehyde 17a21 (2.54 g,
12.0 mmol) in CH2Cl2 (30 mL) was slowly added to a solution
of ethylenediamine (0.76 g, 12.6 mmol) in the same solvent
(20 mL), kept at 0 ꢀC. The resulting mixture was stirred for
20 min and then treated with N-bromosuccinimide (2.32 g,
13.0 mmol) in small portions. After stirring overnight at
room temperature, the hydrobromide of imidazoline 18a was
precipitated by addition of diethyl ether (100 mL) and place-
ment in the refrigerator. The salt was filtered off, washed
with diethyl ether, and separated between ethyl acetate and
satd aq NaHCO3. The organic phase was dried over Na2SO4
and the solvent was evaporated leaving 18a (2.72 g, 90%) as
a colorless solid of mp 52 ꢀC; nmax/cmꢁ1 3431, 2868, 2249,
1602, 1567, 1493; dH (300 MHz, CDCl3) 3.66 (4H, s), 5.12
(2H, s), 5.91 (1H, br s), 6.95e7.00 (2H, m), 7.30e7.45 (6H, m),
8.08 (1H, dd, J¼7.8, 1.9 Hz); dC (75 MHz, CDCl3) 49.3,
71.0, 112.9, 118.8, 121.5, 127.4, 128.3, 128.8, 131.2, 131.8,
136.0, 156.7, 163.6; m/z (EI, 70 eV) 252 (Mþ, 11%), 161
(74%), 133 (38%), 91 (100%). Anal. Calcd for C16H6N2O:
C, 76.2; H, 6.4; N, 11.1. Found: C, 76.0; H, 6.3; N, 11.3%.
4.4.5. 2-(20-Benzoxyphenyl)-1-[30-di(200-hydroxyethyl)amino]-
propanoyl-4,5-dihydroimidazole 20a
Analogously to the synthesis of 3, compound 20a (1.71 g,
65%) was obtained from diethanolamine (735 mg, 7.0 mmol)
and 19a (1.96 g, 6.4 mmol) as a pale yellow viscous oil;
nmax/cmꢁ1 3402, 2948, 2876, 2245, 1664, 1626, 1597, 1492;
dH (300 MHz, CDCl3) 2.08 (2H, t, J¼5.8 Hz), 2.26 (4H, t,
J¼4.9 Hz), 2.53 (2H, t, J¼5.8 Hz), 3.31 (4H, t, J¼4.9 Hz),
3.55 (2H, br s), 3.80e3.90 (4H, m), 5.00 (2H, s), 6.90e7.00
(2H, m), 7.20e7.40 (7H, m); dC (75 MHz, CDCl3) 27.4,
47.2, 49.6, 55.8, 59.2, 67.8, 70.1, 112.2, 120.7, 125.8, 127.0,
128.4, 128.7, 128.9, 131.4, 136.1, 155.8, 156.3, 168.2; m/z
(EI, 70 eV, þMSTFA) 554 (Mþꢁ1, 3%), 540 (5%), 452
(100%), 265 (15%), 262 (10%), 215 (14%), 91 (55%), 73
4.4.2. 2-(20,30-Dibenzoxyphenyl)-4,5-dihydroimidazole 18b
Analogously to 18a, compound 18b (2.60 g, 88%) was ob-
tained from 17b22 (2.64 g, 8.3 mmol) as a pale yellow solid of
mp 58 ꢀC; nmax/cmꢁ1 3435, 2868, 2253, 1599, 1568, 1492,
1454, 1433; dH (300 MHz, CDCl3) 3.60 (4H, s), 5.01 (2H, s),

1718
R. Schobert et al. / Tetrahedron 64 (2008) 1711e1720
(31%). Anal. Calcd for C23H29N3O4: C, 67.1; H, 7.1; N, 10.2.
Found: C, 66.8; H, 7.3; N, 10.4%.
8.0e8.10 (2H, m), 8.21 (2H, t, J¼7.1 Hz); dC (75 MHz,
CDCl3) 34.4, 40.2, 47.2, 50.9, 52.6, 62.3, 70.8, 71.3, 75.9,
76.2, 116.1, 117.3, 121.4, 123.2, 124.4, 126.7, 126.9, 127.3,
127.5, 127.6, 127.8, 128.0, 128.2, 128.8, 129.7, 130.5,
131.4, 132.0, 132.2, 132.7, 136.0, 136.3, 140.1, 143.8,
144.2, 146.2, 151.7, 162.5, 164.8, 165.1, 169.3; m/z (EI,
70 eV) 885 (1%), 386 (4%), 358 (7%), 317 (21%), 226
(14%), 91 (100%). Anal. Calcd for C80H77N5O13: C, 73.0;
H, 5.9; N, 5.3. Found: C, 72.8; H, 6.2; N, 5.4%.
4.4.6. 2-(20,30-Dibenzoxyphenyl)-1-[30-di(200-hydroxyethyl)-
amino]propanoyl-4,5-dihydroimidazole 20b
Analogously to 20a, compound 20b (1.14 g, 54%) was ob-
tained from diethanolamine (473 mg, 4.5 mmol) and 19b
(1.69 g, 4.1 mmol) as a pale yellow foam; nmax/cmꢁ1 3385,
2949, 2877, 2246, 1664, 1626, 1595, 1473; dH (300 MHz,
CDCl3) 2.11 (2H, t, J¼5.9 Hz), 2.32 (4H, t, J¼5.1 Hz), 2.62
(2H, t, J¼5.9 Hz), 3.45e3.60 (4H, m), 3.75 (2H, br s),
3.80e3.90 (4H, m), 5.01 (2H, s), 5.17 (2H, s), 6.95e7.05
(1H, m), 7.10e7.25 (3H, m), 7.30e7.50 (9H, m); dC
(75 MHz, CDCl3) 27.7, 47.3, 50.1, 55.9, 59.0, 67.5, 70.2,
74.3, 112.1, 120.9, 124.7, 126.3, 127.5, 127.8, 128.0, 128.2,
128.3, 128.5, 136.2, 136.8, 147.7, 151.6, 156.1, 168.4; m/z
(EI, 70 eV, þMSTFA) 660 (Mþꢁ1, 1%), 646 (7%), 558
(100%), 413 (22%), 262 (34%), 203 (11%), 91 (87%), 73
(31%). Anal. Calcd for C30H35N3O5: C, 69.6; H, 6.8; N, 8.1.
Found: C, 69.4; H, 7.0; N, 8.0%.
4.4.9. 2-(20-Hydroxyphenyl)-1-{30-di-[800-aza-300-oxa-400,900-
dioxo-900-(2000,3000-dihydroxyphenyl)nonyl]amino}propanoyl-
4,5-dihydroimidazole 15a
Catalytic hydrogenation of 21a (1.40 g, 1.16 mmol) was
performed analogously to the synthesis of 7, 10% Pd on char-
coal catalyst (250 mg) and extended reaction time (36 h) were
required to achieve completion. Compound 15a (827 mg,
95%) was obtained as a colorless foamy solid of mp 136e
138 ꢀC; nmax/cmꢁ1 3358, 2941, 2251, 1729, 1648, 1585,
1456; dH (300 MHz, CD3OD) 1.80e1.90 (4H, m), 2.14 (2H,
t, J¼6.4 Hz), 2.39 (4H, t, J¼6.9 Hz), 2.75e2.95 (6H, m),
3.30e3.40 (4H, m), 3.86 (4H, t, J¼5.1 Hz), 3.90e4.05 (4H,
m), 6.71 (2H, t, J¼8.0 Hz), 6.90e7.10 (5H, m), 7.35e7.45
(2H, m), 7.75e7.85 (1H, m); dC (75 MHz, CD3OD) 25.7,
31.4, 33.0, 40.1, 41.3, 47.2, 47.8, 50.3, 62.3, 116.2, 118.7,
120.1, 120.8, 121.4, 121.9, 122.1, 122.6, 147.0, 147.3,
150.1, 156.0, 162.8, 168.8, 171.9, 174.5. Anal. Calcd for
C38H45N5O12: C, 60.0; H, 5.9; N, 9.2. Found: C, 60.3; H,
5.6; N, 9.1%.
4.4.7. 2-(20-Benzoxyphenyl)-1-{30-di-[800-aza-300-oxa-400,900-
dioxo-900-(2000,3000-dibenzoxyphenyl)non-500-enyl]amino}-
propanoyl-4,5-dihydroimidazole 21a
Analogously to the synthesis of 6, compound 21a (1.45 g,
60%) was obtained from ylide 5 (1.45 g, 4.8 mmol), aldehyde
413 (1.65 g, 4.4 mmol), and diol 20a (0.82 g, 2.0 mmol) as
a pale yellow foam; Rf 0.40 (cyclohexane/ethyl acetate 1:4);
nmax/cmꢁ1 3384, 3034, 2939, 2251, 1719, 1655, 1578, 1528,
1453; dH (300 MHz, CDCl3) 2.16 (2H, t, J¼6.8 Hz), 2.55
(4H, t, J¼5.4 Hz), 2.72 (2H, t, J¼6.8 Hz), 3.80e4.05 (12H,
m), 5.06 (2H, s), 5.11 (4H, s), 5.16 (4H, s), 5.76 (2H, dt,
J¼15.4, 1.6 Hz), 6.75 (2H, dt, J¼15.4, 4.5 Hz), 7.10e7.50
(27H, m), 7.60e7.75 (6H, m), 8.0e8.10 (2H, m), 8.19 (2H,
t, J¼7.0 Hz); dC (75 MHz, CDCl3) 33.9, 40.3, 47.4, 50.8,
52.6, 62.3, 70.2, 71.3, 75.8, 117.3, 118.9, 121.4, 123.3,
124.4, 126.9, 127.5, 127.6, 127.9, 128.2, 128.4, 128.5,
128.7, 128.9, 130.1, 130.3, 131.8, 132.0, 132.2, 136.0,
136.2, 144.0, 151.7, 156.2, 164.6, 165.2, 165.7, 170.1; m/z
(EI, 70 eV) 1208 (Mþꢁ1, 1%), 779 (2%), 417 (4%), 317
(29%), 251 (22%), 235 (31%), 91 (100%). Anal. Calcd for
C73H71N5O12: C, 72.4; H, 5.9; N, 5.8. Found: C, 72.7; H,
6.1; N, 5.6%.
4.4.10. 2-(20,30-Dihydroxyphenyl)-1-{30-di-[800-aza-300-oxa-
400,900-dioxo-900-(2000,3000-dihydroxyphenyl)-nonyl]amino}-
propanoyl-4,5-dihydroimidazole 15b
Analogously to 15a, compound 15b (398 mg, 95%) was
obtained from 21b (710 mg, 0.54 mmol) as a colorless foamy
solid of mp 144e146 ꢀC (CH2Cl2/ethyl acetate); nmax/cmꢁ1
3355, 2940, 2256, 1731, 1647, 1582, 1457; dH (300 MHz,
CD3OD) 1.80e1.90 (4H, m), 2.17 (2H, t, J¼6.3 Hz), 2.39
(4H, t, J¼6.7 Hz), 2.80e3.00 (6H, m), 3.30e3.40 (4H, m),
3.93 (4H, t, J¼5.2 Hz), 3.95e4.10 (4H, m), 6.75 (2H, t,
J¼8.1 Hz), 6.80e7.00 (4H, m), 7.25e7.35 (3H, m); dC
(75 MHz, CD3OD) 25.6, 31.3, 33.0, 40.2, 41.5, 47.3, 47.7,
50.6, 62.2, 114.1, 116.4, 116.8, 118.5, 120.0, 121.2, 121.7,
122.3, 147.2, 147.4, 150.1, 151.2, 162.6, 169.1, 172.0,
174.4. Anal. Calcd for C38H45N5O13: C, 58.5; H, 5.8; N,
9.0. Found: C, 58.7; H, 6.0; N, 8.8%.
4.4.8. 2-(20,30-Dibenzoxyphenyl)-1-{30-di-[800-aza-300-oxa-
400,900-dioxo-900-(2000,3000-dibenzoxyphenyl)-non-500-enyl]-
amino}propanoyl-4,5-dihydroimidazole 21b
Analogously to 21a, compound 21b (723 mg, 55%) was
obtained from ylide 5 (725 mg, 2.4 mmol), aldehyde 413
(825 mg, 2.2 mmol), and 20b (517 mg, 1.0 mmol) as a pale
4.5. Synthesis of the benzamide chelators 16
4.5.1. N-(tert-Butoxycarbonyl)-N,N-{di-[8-aza-3-oxa-4,9-
dioxo-9-(20,30-dibenzoxyphenyl)-non-5-enyl]}amine 23a
Analogously to the synthesis of 6, compound 23a (1.16 g,
58%) was obtained from ylide 5 (1.33 g, 4.4 mmol), aldehyde
413 (1.57 g, 4.2 mmol), and N-Boc-diethanolamine 2223
(410 mg, 2.0 mmol) as a pale yellow foam of Rf 0.42 (cyclo-
hexane/ethyl acetate 1:4); nmax/cmꢁ1 3358, 2972, 1739,
1706, 1653, 1553; dH (300 MHz, CDCl3) 1.42 (9H, s), 3.34
yellow foam; Rf 0.42 (cyclohexane/ethyl acetate 1:4); nmax
/
cmꢁ1 3380, 3034, 2951, 2250, 1719, 1657, 1578, 1529,
1453; dH (300 MHz, CDCl3) 2.12 (2H, t, J¼6.5 Hz), 2.53
(4H, t, J¼5.2 Hz), 2.71 (2H, t, J¼6.5 Hz), 3.79 (4H, t,
J¼5.2 Hz), 3.85e4.05 (8H, m), 5.02 (6H, s), 5.08 (2H, s),
5.15 (4H, s), 5.71 (2H, dt, J¼16.0, 1.8 Hz), 6.74 (2H, dt,
J¼16.0, 4.6 Hz), 7.10e7.50 (31H, m), 7.65e7.80 (6H, m),

R. Schobert et al. / Tetrahedron 64 (2008) 1711e1720
1719
(4H, t, J¼5.4 Hz), 3.95e4.05 (4H, m), 4.26 (4H, t, J¼5.4 Hz),
5.11 (4H, s), 5.16 (4H, s), 5.79 (2H, dt, J¼16.0, 1.9 Hz), 6.81
(2H, dt, J¼16.0, 4.5 Hz), 7.15e7.25 (4H, m), 7.30e7.55 (20H,
m), 7.70e7.75 (2H, m), 8.18 (2H, t, J¼7.1 Hz); dC (75 MHz,
CDCl3) 26.5, 41.3, 50.8, 61.6, 70.5, 74.7, 80.1, 118.0, 120.5,
121.4, 123.4, 124.9, 126.6, 127.3, 127.5, 127.9, 128.3,
128.7, 136.2, 136.5, 144.2, 147.4, 152.1, 154.6, 165.9,
168.2; m/z (EI, 70 eV) 1003 (Mþ, 1%), 947 (3%), 903 (2%),
573 (5%), 473 (13%), 286 (17%), 91 (100%). Anal. Calcd
for C59H61N3O12: C, 70.6; H, 6.1; N, 4.2. Found: C, 71.0;
H, 5.9; N, 4.3%.
1:2); nmax/cmꢁ1 3359, 2933, 1733, 1672, 1635, 1578; dH
(300 MHz, CDCl3) 3.52 (2H, t, J¼5.3 Hz), 3.65 (2H, t,
J¼5.0 Hz), 3.95e4.05 (4H, m), 4.15e4.25 (4H, m), 4.29
(2H, t, J¼5.4 Hz), 5.09 (2H, s), 5.11 (4H, s), 5.16 (2H, s),
5.19 (4H, s), 5.69 (1H, d, J¼15.6 Hz), 5.81 (1H, d,
J¼15.6 Hz), 6.29 (1H, dt, J¼15.3, 1.8 Hz), 6.66 (1H, dt,
J¼15.3, 4.4 Hz), 6.83 (2H, dt, J¼15.6, 4.6 Hz), 7.10e7.25
(6H, m), 7.30e7.50 (30H, m), 7.65e7.75 (3H, m), 8.10e
8.20 (3H, m); dC (75 MHz, CDCl3) 40.4, 40.7, 40.8, 46.3,
47.6, 61.8, 62.3, 71.1, 76.3, 117.9, 118.0, 120.6, 121.4,
121.7, 123.3, 123.6, 124.9, 126.2, 127.4, 127.5, 127.7,
128.1, 128.6, 136.3, 136.5, 142.5, 144.6, 145.2, 146.8,
151.7, 165.1, 165.4, 165.8, 166.6. Anal. Calcd for
C79H74N4O14: C, 72.8; H, 5.7; N, 4.3. Found: C, 72.5; H,
5.3; N, 4.3%.
4.5.2. N-{4-[30-Di-(800-aza-300-oxa-400,900-dioxo-900-(2000,3000-
dibenzoxyphenyl)-non-500-enyl)-amino]-4-oxobut-2-enyl}-2-
(benzoxy)benzamide 25a
Deprotection of compound 23a (1.10 g, 1.1 mmol) was car-
ried out as described for compound 9. Di-[8-aza-3-oxa-4,9-di-
oxo-9-(20,30-dibenzoxyphenyl)-non-5-enyl]amine 23b (0.83 g,
84%) was obtained as a pale yellow foam and used without
further purification; Rf 0.12 (ethyl acetate); nmax/cmꢁ1 3362,
2924, 1736, 1659, 1578, 1463; dH (300 MHz, CDCl3) 2.93
(4H, t, J¼5.4 Hz), 4.00e4.10 (4H, m), 4.24 (2H, t,
J¼5.4 Hz), 5.11 (4H, s), 5.16 (4H, s), 5.85 (2H, dt, J¼15.6,
1.8 Hz), 6.83 (2H, dt, J¼15.6, 4.9 Hz), 7.10e7.20 (4H, m),
7.35e7.55 (20H, m), 7.70e7.75 (2H, m), 8.20 (2H, t,
J¼6.9 Hz); dC (75 MHz, CDCl3) 41.2, 48.4, 61.8, 70.6, 74.7,
118.1, 120.5, 121.3, 123.6, 124.7, 126.1, 127.2, 127.5,
127.7, 128.1, 128.7, 136.1, 136.3, 144.0, 147.2, 151.6,
165.9, 168.2. Compound 23b (0.40 g, 0.44 mmol) was submit-
ted to a three-component reaction with ylide 5 (160 mg,
0.53 mmol) and aldehyde 24 (130 mg, 0.48 mmol) as de-
scribed for compound 6. Yield: 347 mg (66%), pale yellow
foam; Rf 0.44 (cyclohexane/ethyl acetate 1:2); nmax/cmꢁ1
3362, 2931, 1733, 1676, 1638, 1577; dH (300 MHz, CDCl3)
3.50 (2H, t, J¼5.4 Hz), 3.64 (2H, t, J¼5.0 Hz), 3.85e3.95
(2H, m), 3.95e4.05 (2H, m), 4.10e4.20 (4H, m), 4.28 (2H,
t, J¼5.4 Hz), 5.10 (2H, s), 5.11 (2H, s), 5.16 (2H, s), 5.18
(4H, s), 5.68 (1H, d, J¼15.5 Hz), 5.83 (1H, d, J¼15.5 Hz),
6.33 (1H, dt, J¼15.2, 1.7 Hz), 6.68 (1H, dt, J¼15.2, 4.4 Hz),
6.83 (2H, dt, J¼15.5, 4.7 Hz), 7.00e7.10 (2H, m), 7.15e
7.25 (4H, m), 7.30e7.50 (26H, m), 7.65e7.75 (3H, m),
3.10e8.20 (3H, m); dC (75 MHz, CDCl3) 40.1, 40.3, 40.7,
46.1, 47.5, 61.8, 62.4, 71.2, 71.3, 76.5, 112.9, 117.3, 120.6,
120.7, 120.9, 121.2, 121.8, 123.2, 123.3, 126.7, 127.4,
127.6, 127.8, 128.4, 128.6, 128.9, 129.0, 129.1, 129.3,
132.0, 132.8, 135.7, 136.2, 136.4, 142.3, 144.8, 145.3,
146.9, 151.7, 156.8, 165.1, 165.3, 165.4, 165.7, 166.5. Anal.
Calcd for C72H68N4O13: C, 72.2; H, 5.7; N, 4.7. Found: C,
72.5; H, 5.9; N, 4.5%.
4.5.4. N-{4-[30-Di-(800-aza-300-oxa-400,900-dioxo-900-(2000,3000-
dihydroxyphenyl)-nonyl)amino]-4-oxobutyl}-2-(hydroxy)-
benzamide 16a
Analogously to the synthesis of 7, compound 16a (190 mg,
90%) was obtained from 25a (335 mg, 0.28 mmol) as a color-
less foamy solid of mp 124e126 ꢀC; nmax/cmꢁ1 3378, 2944,
1719, 1644, 1619, 1585; dH (300 MHz, CD3OD) 1.80e1.95
(6H, m), 2.30e2.40 (4H, m), 2.49 (2H, t, J¼6.0 Hz), 3.35e
3.45 (4H, m), 3.55e3.70 (6H, m), 4.14 (4H, t, J¼5.5 Hz),
6.68 (2H, dt, J¼8.1, 1.2 Hz), 6.80e6.95 (4H, m), 7.18 (2H,
dt, J¼8.1, 1.2 Hz), 7.25 (1H, dt, J¼7.9, 1.2 Hz), 7.70e7.80
(1H, m); dC (75 MHz, CD3OD) 25.7, 26.1, 31.6, 32.4, 39.7,
39.8, 46.7, 46.8, 63.2, 116.8, 117.0, 118.6, 118.8, 119.0,
119.7, 120.2, 128.8, 134.9, 147.4, 150.5, 160.4, 171.7,
174.6, 174.9, 175.1. Anal. Calcd for C37H44N4O13: C, 59.0;
H, 5.9; N, 7.4. Found: C, 59.2; H, 6.0; N, 7.1%.
4.5.5. N-{4-[30-Di-(800-aza-300-oxa-400,900-dioxo-900-(2000,3000-
dihydroxyphenyl)-nonyl)amino]-4-oxobutyl}-2,3-
(dihydroxy)benzamide 16b
Analogously to 16a, compound 16b (177 mg, 92%) was
obtained from 25b (325 mg, 0.25 mmol) as a colorless foamy
solid of mp 133e135 ꢀC; nmax/cmꢁ1 3372, 2948, 1722, 1643,
1625, 1584; dH (300 MHz, CD3OD) 1.80e1.95 (6H, m),
2.30e2.45 (4H, m), 2.51 (2H, t, J¼6.0 Hz), 3.35e3.50 (6H,
m), 3.55e3.65 (4H, m), 4.16 (4H, t, J¼5.3 Hz), 6.66 (3H, t,
J¼7.9 Hz), 6.91 (3H, dd, J¼7.9, 1.1 Hz), 7.18 (3H, dd,
J¼7.9, 1.1 Hz); dC (75 MHz, CD3OD) 25.8, 26.1, 31.6, 32.4,
39.8, 40.2, 46.7, 46.9, 63.2, 116.8, 118.7, 118.8, 119.8,
147.4, 150.5, 171.3, 174.5, 174.7, 175.0. Anal. Calcd for
C37H44N4O14: C, 57.8; H, 5.8; N, 7.3. Found: C, 58.1; H,
5.8; N, 7.4%.
4.6. Agar diffusion assay
4.5.3. N-{4-[30-Di-(800-aza-300-oxa-400,900dioxo-900-(2000,3000-
dibenzoxyphenyl)-non-500-enyl)-amino]-4-oxobut-2-enyl}-
2,3-(dibenzoxy)benzamide 25b
Analogously to 25a, compound 25b (332 mg, 58%) was
obtained from amine 23b (0.40 g, 0.44 mmol), ylide 5
(160 mg, 0.53 mmol), and aldehyde 4 (180 mg, 0.48 mmol)
as a pale yellow foam; Rf 0.42 (cyclohexane/ethyl acetate
Agar plates containing 20 mL of MuellereHinton II me-
dium (BD-Diagnostics, Heidelberg) with or without EDDA
(LaboTest OHG, Niederschona; 100 mg mLꢁ1) were inocu-
lated with 100 mL of the respective bacteria suspension in liq-
uid broth (opacity: Mc Farland 0.5) using a Drigalski spatula.
Test samples were prepared as solutions of the respective
¨

1720
R. Schobert et al. / Tetrahedron 64 (2008) 1711e1720
compound in ethanol at 10, 5, 2.5, and 1 mg mLꢁ1. Each solu-
tion (15 mL) was applied onto sterile 6 mm cellulose discs (CT
0998 B, Oxoid, Wesel). The ethanol was allowed to evaporate
and the discs were placed upon the inoculated agar plate. The
diameters in millimeter of the resulting growth and/or inhibi-
tion zones were determined after 48 h of incubation at 36 ꢀC.
M. C.; Jacques, M.; Darwish, I.; Dolence, E. K.; Dolence, J. A.; Ghosh, A.;
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Acknowledgements
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We are indebted to Prof. Klaus Hantke, Department of
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¨
viding us with various E. coli strains. We are also grateful to
the Deutsche Forschungsgemeinschaft for financial support
(grant Scho 402/7).
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