FULL PAPER
tanium (2c) complexes of enter-
obactin. By comparing the M–
Ent interactions, taking into ac-
count the rigidity of the triseryl
macrolactone ring[3] and alter-
nating the metal, we derived
trends for the binding proper-
ties. To obtain a more detailed
understanding, we carried out a
series of quantum-chemical
model calculations, which al-
lowed for correlating the effec-
tive ionic radius[10] of the metal,
structural changes in the corre-
sponding M–Ent complex, and
the computed binding energies.
SiIV is the smallest cation
known to bind to enterobactin.
The metal unspecific binding
behavior of Ent is interesting
and offers a unique opportunity
for studying the chemical be-
havior of Ent in detail. Silicon
lacks unpaired valence elec-
trons and low-energy, electroni-
cally excited states that contin-
ue to make mechanistic work
on Fe-binding difficult. Thus,
we anticipate that silicon bind-
ing will provide a convenient
platform for studying how Ent
binds highly charged metal ions.
Given the radically different
electronic features between sili-
Scheme 2. a) Synthesis of compound 1 and of the potassium salts of 2a–c: i) DIC, HOBt, Et3N, CH2Cl2, RT, ii)
H2, Pd/C, EtOAc, EtOH, iii) SiACHTUNGTRENNN(UG OMe)4, KOH, MeOH, RT, iv) GeACHTUNRGTEG(NNUN OMe)4, KOH, MeOH, RT, v) TiACHTUNGTRENNUNG(OiPr)4,
KOH, MeOH, RT. b) Synthesis of 15N-labeled enterobactin 11: vi) MeOH, SOCl2, RT; vii) TrtCl, Et3N, DCM,
RT, viii) stannoxane, m-xylene, reflux, ix) 1.5m HCl/EtOH, reflux. DIC= N,N’-diisopropylcarbodiimide,
HOBt=1-hyroxybenzotriazole.
con and iron, we suspect that the silicon binding may be no-
tably different from iron binding. A promising way of under-
standing these differences is our combined experimental and
computational approach. TiIV–Ent is an important member
in our systematic study, as the TiIV d0 center lacks unpaired
valence electrons, as does silicon, but it can access d-orbitals
that will be important in FeIII–Ent. In addition, TiIV–Ent
should in principle be a better model for FeIII–Ent than VIV–
Ent that was studied previously, as the ionic radius of TiIV is
a closer to that of iron.[10]
Treatment of enterobactin with Si
TiAHCTUNGETRNN(GUN OiPr)4 in the presence of a stoichiometric amount of
ACHUTNGTNERNUG(OMe)4, GeACHTUNGTRNEN(UGN OMe)4, and
KOH provided the potassium salts of 2a–c in quantitative
yields. This synthetic protocol enabled the preparation of
the Si, Ge, and Ti complexes by a simple purification proce-
dure. High-resolution ESI-MS, as well as H and 13C NMR
1
spectra of 2a–c (see Supporting Information) reveal compa-
rable sets of signals and are in support of the corresponding
structures of 2a, 2b, and 2c (Scheme 2). The NMR spectra
confirmed the presence of intramolecular hydrogen bonding
between the amide protons and the ortho catecholate
oxygen atoms in the complexes (Figure 1).
Results and Discussion
To study the reactions of enterobactin with Si, Ge, and Ti,
time-dependent NMR studies were performed. As we
Enterobactin 1 was synthesized from acid 3[11] in two steps
(Scheme 2). The macrocyclic lactone salt 4 was prepared ac-
cording to previously published protocols.[12a] Coupling of 4
to benzyl-protected acid 3 by means of DIC/HOBt provided
the fully protected enterobactin 5 in 90% yield. These cou-
pling conditions resulted in higher yields compared to previ-
ously described procedures employing acid chlorides, in
which the maximal reported yield was 79%.[12] Compound 5
was transformed into Ent 1 by hydrogenolysis.[12]
showed previously, Ent reacts with Si
addition of base to afford the protonated form H CTHUNGTRENNUNG
compare the rate of formation of 2a–c, three NMR experi-
ments were performed (see the Supporting Information).
ACHTUNGTRENNUNG
Solutions of 1 in [D6]DMSO were treated with SiACHTUNGTRENNUNG(OMe)4,
GeACHTNUTRGENN(UG OMe)4, and TiACHTUNGTNER(NUGN OiPr)4, respectively. The formation of
the GeIV–Ent and TiIV–Ent complexes was completed within
1 h, whereas SiIV–Ent was formed within 24 h.
Chem. Eur. J. 2013, 19, 10536 – 10542
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10537