Synthesis and structural characterization of hexacoordinate silicon, germanium, and titanium complexes of the E. coli siderophore enterobactin

Article abstract of DOI:10.1002/chem.201301825

The E. coli siderophore enterobactin, one of the strongest Fe^III chelators known to date, is also capable of binding Si^IV under physiological conditions. We report on the synthesis and structural characterization of the tris(catecholate) Si^IV-enterobactin complex and its Ge^IV and Ti^IV analogues. Comparative structural analysis, supported by quantum-chemical calculations, reveals the correlation between the ionic radius and the structural changes in enterobactin upon complexation. Copyright

Full text of DOI:10.1002/chem.201301825

DOI: 10.1002/chem.201301825
Synthesis and Structural Characterization of Hexacoordinate Silicon,
Germanium, and Titanium Complexes of the E. coli Siderophore
Enterobactin
Todor Baramov,[a] Karlijn Keijzer,[b] Elisabeth Irran,[a] Eva Mçsker,[a]
Mu-Hyun Baik,*[b, c] and Roderich Sꢀssmuth*[a]
Abstract: The E. coli siderophore enterobactin, one of the strongest FeIII chelators
known to date, is also capable of binding SiIV under physiological conditions. We
Keywords: enterobactin · germani-
report on the synthesis and structural characterization of the tris(catecholate) SiIV–
um · siderophores · silicon · titani-
enterobactin complex and its GeIV and TiIV analogues. Comparative structural anal-
um
ysis, supported by quantum-chemical calculations, reveals the correlation between
the ionic radius and the structural changes in enterobactin upon complexation.
Introduction
Iron is the fourth most abun-
dant element on Earth, but it is
not readily bio-available due to
the low solubility of FeIII salts
at neutral and basic pH. In re-
sponse, bacteria evolved iron
extraction strategies using side-
rophores, which are low-molec-
ular weight chelating agents
that exhibit high FeIII-binding
Scheme 1. Structure formulae of enterobactin 1 (Ent) and its Si, Ge, and Ti complexes 2a, 2b, and 2c.
affinities.[1] For example, enteric
bacteria such as E. coli and Sal-
monellae produce the hexadentate enterobactin (Ent, 1),
which is considered to be the strongest ferric chelator with
an estimated Kd as low as 10À49 m (Scheme 1).[2] Its triseryl
macrolactone backbone bears three 2,3-dihydroxybenzoyl
(Dhb) residues that become catecholate ligands after depro-
tonation to form an octahedral hexacoordinate high-spin
FeIII complex.[2] Despite significant efforts, the structure of
the FeIII–Ent complex has not been determined successfully
to date. The only crystal structure of a metal–enterobactin
complex available is the VIV–Ent complex, which is com-
monly used as a model for the structure of FeIII–Ent.[3] Al-
though the main biological function of enterobactin is to ef-
fectively transport FeIII, it was found to bind many other
metal ions with varying affinities.[4] Recently, we found that
Ent binds silicon to form the hexacoordinate complex SiIV–
Ent (2a) at physiological pH,[5] representing the first exam-
ple of a natural product bound to silicon under physiological
conditions, which makes it an interesting model for compari-
son with other hexacoordinate silicon complexes.[6] Along
with the interest in higher coordinate silicon compounds,
many studies have focused on the synthesis and characteri-
zation of hexacoordinate catecholate germanium and titani-
um complexes.[7–9] Attachment of enterobactin and other
catecholate-type compounds to oxidic surfaces, for example,
TiO2 is of interest with respect to bacterial biofilm forma-
tion, generation of antimicrobial surfaces, and immobiliza-
tion of catalysts.[9c–e]
[a] T. Baramov, Dr. E. Irran, E. Mçsker, Prof. Dr. R. Sꢀssmuth
Technische Universitꢁt Berlin, Fakultꢁt II, Institut fꢀr Chemie
Strasse des 17. Juni 124, 10623 Berlin (Germany)
Fax : (+49) 30-314-79651
E-mail: suessmuth@chem.tu-berlin.de
[b] K. Keijzer, Prof. Dr. M.-H. Baik
Department of Chemistry
Indiana University, Bloomington, IN 47405 (USA)
E-mail: mbaik@indiana.edu
[c] Prof. Dr. M.-H. Baik
Department of Materials Chemistry, Korea University
Jochiwon-eup, Sejong-si, 339-700 (South Korea)
Herein, we present the synthesis and X-ray crystallo-
graphic analysis of the silicon (2a), germanium (2b), and ti-
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201301825.
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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.
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M.-H. Baik, R. Sꢀssmuth et al.
Figure 1. Comparison between the 1H NMR spectra (400.1 MHz) of en-
terobactin and the potassium salts of 2a (SiIV–Ent), 2b (GeIV–Ent), and
2c (TiIV–Ent) in [D6]DMSO.
Complexes 2a–c were crystallized from DMF/Et2O yield-
ing K
2A
and K2ACHTUNGTRENNUNG[Ti–Ent]·3DMF, respectively (see the Supporting In-
formation).[13] Complexes 2a and 2b crystallized in the
space group P212121, whereas 2c crystallized in space group
P21. The high-resolution structures (Figure 2) reveal that the
metal ions are coordinated to the catechol moieties. All
three complex anions (2a–c) display twisted octahedral ge-
ometry, approximate C3 point symmetry, and D configura-
tion of the metal centers, which is in good agreement with
the previously characterized VIV–Ent complex.[3] Our quan-
tum-chemical simulations reliably reproduce all crystal
structures (Figure 2d).
As seen from the single-crystal structures of SiIV–Ent,
GeIV–Ent, and TiIV–Ent, the chirality of the l-serines uni-
formly induces complexes with D configuration at the metal
centers. This is consistent with the D absolute configuration
of the FeIII–, CrIII–, and RhIII–Ent complexes, which was con-
firmed by CD spectroscopy.[14] It was previously demonstrat-
ed that the D configuration of FeIII–Ent is crucial for the bi-
ological activity of the siderophore.[15] Our findings support
the notion that the stereochemistry is primarily determined
by the chirality of the l-serine base. Comparison of the SiIV–
, GeIV–, and TiIV–Ent complexes with the X-ray structure of
the VIV–Ent complex[3] can provide insights into important
molecular features relevant for FeIII chelation by enterobac-
tin. Among all four metals, SiIV (0.40 ꢃ) has the smallest
ionic radius compared to GeIV (0.53 ꢃ), VIV (0.58 ꢃ), and
TiIV (0.61 ꢃ).[10]
Figure 2. Side (left) and bottom (right) views of the molecular structures
in the crystals of a) SiIV–Ent 2a, b) GeIV–Ent 2b and c) TiIV–Ent 2c
(probability level of displacement ellipsoids 50%), d) overlay of the cal-
culated structures of SiIV–Ent (magenta), GeIV–Ent (blue), and TiIV–Ent
(green).
The crystallographic data reveals that the main differen-
ces in the structures are in the M–O distances (Table 1) and
the dihedral angle C8-N1-C7-O3 (Table 2). SiIV–Ent has the
IV
À
shortest and Ti –Ent the longest M O bonds, which is con-
sistent with the differences in the ionic radii. The distance
between the metal and the ortho catechol oxygen (M–O1) is
generally longer than the distance between the metal and
the meta catechol oxygen (M–O2). The bite angle (O1-M-
O2) for SiIV–Ent is 86.8(2)8, whereas the TiIV–Ent complex
has a bite angle of 78.9(2)8 caused by the larger effective
radius of TiIV. Hence short M–O distances, caused by rela-
tive small ionic radius of M, give rise to larger bite angles
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Metal–Enterobactin Complexes
FULL PAPER
Table 1. Comparison between selected average bond lengths [ꢃ] in the
structures of the SiIV–, GeIV–, VIV–, and TiIV–enterobactin complexes. For
the torsion angles the absolute values are given.
structures. The distortion of the backbone is directly propor-
tional to the radius of the metal ion following the trend Si<
Ge<Ti (Table 3). The distortion in the backbone is most
SiIV–Ent
GeIV–Ent
VIV–Ent[a]
TiIV–Ent
severe for the TiIV–Ent complex with the RMSD
ACTHUNRTGNE(GNU backbone)
Bond
M[b]–O1
M[b]–O2
C8–C9
C8–C10
O5–C9
O5–C10
1.785(5)
1.771(6)
1.529(11)
1.486(11)
1.345(10)
1.467(9)
1.899(5)
1.879(5)
1.523(11)
1.521(11)
1.333(9)
1.449(9)
1.946(3)
1.939(3)
1.537
1.498
1.341
1.983(6)
1.954(6)
1.518(13)
1.515(12)
1.317(10)
1.452(10)
Table 3. Comparison of the structural distortions imposed on binding Si,
Ge, and Ti to enterobactin.
Complex
[Si–Ent]2À
[Ge–Ent]2À
[Ti–Ent]2À
RMSD
(cavity) [ꢃ]
RMSDACTHGNUTERNNU(G backbone) [ꢃ]
1.457
E
0.177
0.253
0.275
0.299
0.324
[a] Data as published by Raymond et al.[3] [b] M=Si, Ge, V, Ti.
AHCTUNGTRENNUNG
E
5.84ꢄ10À5
Table 2. Comparison between selected average bond angles [8] in the
structures of the SiIV–, GeIV–, VIV–, and TiIV–enterobactin complexes. For
the torsion angles the absolute values are given.
being 0.324 ꢃ. Interestingly, the binding cavity structure for
TiIV is closest to what it would prefer when bound to three
Angle
SiIV–Ent
GeIV–Ent
VIV–Ent[a]
TiIV–Ent
free catechol ligands with the RMSDACTHNUTRGNEUNG(cavity) being practi-
O1-M[b]-O2
86.8(2)
85.5(2)
79.8(1)
116.3(3)
115.6(3)
67.0
175.9
4.0
78.9(2)
cally zero (5.84ꢄ10À5 ꢃ). In contrast, the binding geometry
M[b]-O1-C1
113.0(4)
113.7(5)
66.4(8)
175.2(7)
13.6(12)
111.2(4)
111.6(5)
66.7(8)
179.4(7)
11.1(13)
116.0(5)
116.9(5)
65.1(10)
176.1(7)
3.7(13)
that Ent offers to GeIV is the least favorable in the series
M[b]-O2-C2
C9-C8-C10-O5
C10-O5-C9-C8
C8-N1-C7-O3
with an RMSD
ACHTUNGTRENN(UNG cavity) of 0.253 ꢃ (Table 3). The RMSD for
the binding cavity of Si is smaller than for Ge, which is easy
À
À
to understand: As Si O bonds are stronger than Ge O
bonds, Si should be more effective in enforcing a binding
cavity geometry that is structurally closer to what it prefers
if the catecholates were not restrained by the backbone.
These results are supported by a comparison of the crystal
[a] Data as published by Raymond et al.[3] [b] M=Si, Ge, V, Ti.
(Table 2). The dihedral angle of the amide bond which
should be close to 08 is 13.6(12)8 in the SiIV–Ent and 3.7(13)
in TiIV–Ent (Table 2). The effective ionic radius of TiIV is the
closest to the ionic radius of FeIII (0.65 ꢃ) and therefore the
structure of TiIV–Ent is expected to best approximate the
structure of the FeIII–Ent. Taking into account these obser-
vations it could be expected that the C8-N1-C7-O3 angle
would be closer to 08 in FeIII–Ent.
[17]
[18]
structures of SiIV
TiIV–Ent, respectively. The values of the bite angles and the
average M–O distances in TiIV(cat)3 and TiIV–Ent are closer
(cat)3 and TiIV(cat)3 with SiIV–Ent and
ACHUTGTNRENNUG CAHTUNGTRENNUGN
AHCTUNGTRENNUNG
compared to the corresponding parameters for SiIV
ACTHNUTRGNEU(GN cat)3 and
SiIV–Ent (Table 4). In summary, distortions in the backbone
Previous experimental studies on ferric binding by entero-
bactin and its analogues, demonstrated that substitution of
the macrolactone ring for platforms with different flexibility
affects the binding affinity of the ligand due to steric con-
strains.[16a–d] In addition, molecular mechanics studies com-
paring FeIII binding by different (synthetic) enterobactin an-
alogues[16f] showed that the structural distortion that is
caused upon binding a metal to enterobactin can be separat-
ed into two components: i) the amount of distortion im-
posed on the ligand characterized by the change of the tri-
seryl-backbone structure from its equilibrium geometry and
ii) the amount of distortion in the immediate coordination
sphere of the metal enforced by the structural rigidity of
Ent.[16] The latter is interesting, as it quantifies the effect of
tethering three catechol ligands within the Ent structure and
can be assessed by comparing the geometry of the catechols
around the metal in the M–Ent complex with the geometry
the metal would adopt if they were not restrained by a back-
bone, that is, a metal bound to three free catechol ligands.
The most favorable M–Ent complex should have 1) a mini-
mal distortion of the backbone and 2) minimal deviation
from the preferred coordination geometry specific to the
metal.
À
Table 4. Comparison between average M O bond lengths [ꢃ] and bite
[17a,18]
angles [8] in the structures of M
G
and M–Ent.
[b]
[c]
Parameter SiIV (cat)3
SiIV–Ent
1.778(6) 0.006 1.966(27)
86.8(2) 1.8 80.3(2)
D
TiIV
(cat)3
TiIV–Ent
1.968(6) 0.002
78.9(2) 1.4
D
M[a]-O
1.784(3)
88.6(0.2)
O-M[a]-O
ACHTUNGTRENNUNG
[a] M=Si, Ti. [b] Data as published by Boer et al.[17a] [c] Data as publish-
ed by Raymond et al.[18]
of enterobactin caused by metal-binding are small and are
only slightly affected by the type of cation that is bound. In
general, smaller ions give less distortion. The main energetic
contribution to complex formation originates from the capa-
bility of enterobactin to provide a coordination geometry of
the catechol ligands around the metal that maximizes the
electronic M–O interactions, which is also dependent on the
ability of the metal to enforce such a binding cavity.
Figure 3 summarizes the quantum-chemically calculated
energies for the metal-binding process. Our calculations in-
dicate that electronically,[19] TiIV binding is 72 and 156 kcal
molÀ1 more favorable than SiIV and GeIV, respectively (Fig-
ure 3a).[20] These energies are in good agreement with the
expectation that the octahedral, six-coordinate binding site
in Ent is most suited to bind transition metals that can uti-
lize d-orbitals in addition to the s and p orbitals to form M–
O s bonds. Between the main group metals, Si will from
To quantify these trends, we used our quantum-chemically
calculated structures to first determine the root mean
square deviation (RMSD) between the various metal-bound
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M.-H. Baik, R. Sꢀssmuth et al.
methanolic solutions and formation of 15N-labeled Ent com-
plexes is observed. In contrast, no exchange is detected for
the SiIV–, GeIV–, TiIV–, and VIV–Ent complexes. These results
are in agreement with the previously stated kinetic lability
of Fe–siderophore complexes due to the high-spin d5 config-
uration of the ferric ion, which places electrons in M–L anti-
bonding orbitals that assist M–L bond cleavage reactions.[22]
It is therefore not surprising that crystallization of Ent com-
plexes has been achieved only with the elements, which
form kinetically inert complexes.
To assess whether or not M–binding is reversible, the
above mentioned M–Ent complexes (M=Si, Ge, Ti, V, Fe,
Ga) were each treated with Si
ACHUTNGTNERNUG(OMe)4, GeACHTUNGTRNEN(UGN OMe)4, Ti-
A
ACHTUNGTRENNUNG
room temperature (see the Supporting Information). Simi-
larly to our previous observations for SiIV–Ent and SiIV–
Sal,[5] all six complexes were stable in aqueous solution and
no exchange of the bound metal could be detected, suggest-
ing that the M–Ent binding is irreversible under normal con-
ditions. However, the FeIII– and GaIII–Ent complexes could
be converted into the corresponding GeIV– and TiIV–Ent
complexes upon treatment with GeACHTNUGTRENNUG(OMe)4 and TiACHTUGNTERN(NUGN OiPr)4 in
MeOH. Moreover the conversion of the FeIII–Ent into TiIV–
Ent could be monitored by time-dependent CD spectrosco-
py (Figure 4). This remarkable observation can be under-
stood considering that the electrostatic interaction of FeIII
and GaIII with the polyanionic ligand is much smaller than
for GeIV and TiIV. Replacement of the 3+ metals with the
4+ metals is irreversible and neither FeIII nor GaIII are able
to displace GeIV or TiIV. As the solvation energy differences
between the 3+ and 4+ cations are expected to be less pro-
nounced in the lower dielectric medium, it is understandable
that these metal-exchange reactions are seen in methanol,
but not in water.
Figure 3. Qualitative picture of the reaction profile for formation of M–
Ent complexes. SiIV–Ent gives the smallest DG(Sol) [kcalmolÀ1
in
DMSO.
G
]
stronger bonds, as SiIV is a harder Lewis acid than GeIV
making it a better binding partner for the relatively hard O-
based Lewis bases. To understand the metal-binding experi-
ments mentioned above, we must consider that the metal
ions initially exist as complexes of MACTHNUTRGNEUNG
(OMe)4.[21] Thus, the
experimental observations depend not only on the M–Ent
binding, but also on the M–OMe bond cleavage (Figure 3b).
The M–O binding preference of SiIV over GeIV is even more
pronounced in the methoxy complex with an electronic
binding energy difference of 102 kcalmolÀ1. As a conse-
quence, the overall gain in solution phase free energy DG-
Conclusion
A
The characterization of the SiIV–, GeIV–, and TiIV–Ent com-
plexes presented herein facilitates comparative studies of
Ent complexes with different metals. Our studies give in-
sights into structural changes of Ent upon binding of metals
that have different ionic radii. The kinetic inertness and the
thermodynamic stability of the M–Ent (M=Si, Ge, Ti) com-
plexes were tested by competition experiments. Quantum-
chemical analysis of the M–Ent (M=Si, Ge, Ti) complexes
showed that the formation of SiIV–Ent is least favorable be-
ure 3c). The favorable binding energy for SiIV on the reac-
tant side (Figure 3b) also explains the slow kinetics ob-
served in the experiment, since it will be harder to break
À
À
the Si O bonds in Si
ACHTUNGRTEN(NUNG OMe)4 compared to the Ge O bonds
in Ge(OMe)4.
ACHTUNGTRENNUNG
To experimentally estimate the thermodynamic and kinet-
ic properties of compounds 2a–c compared to the VIV–,
GaIII–, and FeIII–Ent complexes, they were prepared as trie-
thylammonium salts and their formation was controlled by
ESI-MS and CD spectroscopy (see the Supporting Informa-
tion). 15N-labeled enterobactin-probe 11 was synthesized
from 15N-labeled serine 6 in six steps (Scheme 2) and sub-
jected to an exchange reaction with M–Ent complexes (M=
Si, Ge, Ti, V, Fe, Ga) monitored by ESI-MS (see the Sup-
porting Information). Stoichiometric amounts of the labeled
ligand were incubated with the M–Ent complexes for 24 h in
methanolic and aqueous solutions. FeIII– and GaIII–Ent are
labile with respect to Ent exchange in both aqueous and
cause of the high stability of the reactant, SiACTHNUGTRENUNG(OMe)4, which
makes the overall gain in energy for binding to enterobactin
the smallest for SiIV. The slow reaction kinetics of SiIV–Ent is
À
a result of the strong Si O bonds present in the reactant
complex, the lack of electrons in M–L antibonding orbitals
and the 4+ charge compared to the natural binding partner
FeIII. These properties make SiIV–Ent an excellent model to
study the binding mechanism of metals by enterobactin,
which is subject to our ongoing studies, as well as an inter-
esting example of a stable hexacoordinate silicon complex.
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Metal–Enterobactin Complexes
FULL PAPER
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Figure 4. Conversion of FeIII–Ent into TiIV–Ent, monitored by CD spectroscopy. Reaction of 0.15 mm metha-
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ACTHNUTRGENUN(G OiPr)4 (12 mL, 0.18 mmol).
After 8 h the bands at 420 and 530 nm, characteristic of FeIII–Ent disappear. The absorption bands at 341 and
414 nm are indicative of TiIV–Ent. Isosbestic point at 377 nm could be observed.
[12] a) R. J. A. Ramirez, L. Karama-
nukyan, S. Ortiz, C. G. Gutierrez,
Experimental Section
Tetrahedron Lett. 1997, 38, 749–752; b) E. J. Corey, S. Bhattachar-
yya, Tetrahedron Lett. 1977, 45, 3919–3922; c) W. H. Rastetter, T. J.
Erickson, M. C. Venuti, J. Org. Chem. 1980, 45, 5011–5012; d) W. H.
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3579–3590; e) A. Shanzer, J. Libman, J. Chem. Soc. Chem.
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T. T. Lau, C. G. Gutierrez, J. Org. Chem. 1996, 61, 3548–3550.
For full experimental details see the Supporting Information
[13] X-ray quality crystals of the potassium salts of 2a and b were grown
from DMF by vapor diffusion of Et2O at 178C over two weeks.
Data for the single-crystal structure determination of 2a–c were
collected on an Oxford-Diffraction Xcalibur diffractometer, equip-
ped with a CCD area detector Sapphire S and a graphite monochro-
mator utilizing MoKa radiation (l=0.71073 ꢃ). Suitable crystals
were attached to glass fibers using perfluoropolyalkylether oil
(ABCR) and transferred to a goniostat where they were cooled to
150 K for data collection. Software packages used: CrysAlis CCD
for data collection, CrysAlis Pro for cell refinement and data reduc-
tion. The crystal structure was solved by Direct Methods and refined
on F2 using full-matrix least squares with SHELXL97. Absorption
correction was done semi-empirically from equivalents. CCDC-
Acknowledgements
This research was supported by grants of the Deutsche Forschungsge-
meinschaft (DFG SU239/10–1) and DAAD with fellowship to T. B. We
thank Dr. Sebastian Kemper, TU Berlin (Germany), and Prof. Dr.
Hermen Overkleeft, Leiden University (The Netherlands), for helpful
discussions. We thank the National Science Foundation (CHE-0645381),
the Research Cooperation (Scialog Award) and the National Research
Foundation of Korea (WCU Award R31–2012–000–10035–0) for support.
[1] R. C. Hider, X. Kong„ Nat. Prod. Rep. 2010, 27, 635–657.
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1970, 38, 989–992; b) I. G. OꢅBrien, F. Gibson, Biochim. Biophys.
Acta 1970, 215, 393–402; c) K. N. Raymond, E. A. Dertz, S. S. Kim,
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1842–1851.
910685 (K
N
2ACHTUNGTREN[NUNG 2c]·3DMF) and
CCDC-910687 (K2ACTHUNGTR[UNENNG 2a]·4DMF·Et2O·H2O) contain the crystallo-
graphic data for this publication. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif. Selected data for
K2ACHTUNGTRENNUNG[Si
–Ent]·4DMF·Et2O·H2O: single crystal of dimensions 0.62ꢄ0.37ꢄ
0.26 mm3, C46H61K2N7O21Si, Mr =1154.31, orthorhombic, space
group P212121, a=12.2921(7), b=18.9949(13), c=23.5416(15) ꢃ, V=
[4] H. J. Rogers, C. Synge, V. E. Woods, Antimicrob. Agents Chemother.
1980, 18, 63–68.
5496.7(6) ꢃ3, Z=4, 1calcd =1.395 gcmÀ3 m=0.276 mmÀ1
, , FACHTUNGTRENNUNG(000)=
2424, 2qmax =24.998, collected reflections 23040, unique reflections
9613 (Rint =0.1063), restraints 805, parameters 850, S=1.056, R1 (I>
2s(I))=0.0874, wR2 (all data)=0.1271, max./min. residual electron
[5] T. Schmiederer, S. Rausch, M. Valdebenito, Y. Mantri, E. Mçsker, T.
Baramov, K. Stelmaszyk, P. Schmieder, D. Butz, S. I. Mꢀller, K.
Schneider, M.-H. Baik, K. Hantke, R. D. Sꢀssmuth, Angew. Chem.
2011, 123, 4317–4321; Angew. Chem. Int. Ed. 2011, 50, 4230–4233.
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Chem. 2007, 46, 5419–5424.
density 0.469/À0.607 eꢃÀ3
.
Selected data for
K2ACHTUNGTRENNUNG[Ge–En-
t]·6DMF·H2O: single crystal of dimensions 0.55ꢄ0.18ꢄ0.13 mm3,
C48H65GeK2N9O22, Mr =1270.88, orthorhombic, space group P212121,
Chem. Eur. J. 2013, 19, 10536 – 10542
ꢂ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
10541

M.-H. Baik, R. Sꢀssmuth et al.
a=12.7262(9), b=17.6723(14), c=25.0846(16) ꢃ, V=5641.5(7) ꢃ3,
341–355; f) B. P. Hay, D. A. Dixon, R. Vargas, J. Garza, K. N. Ray-
mond, Inorg. Chem. 2001, 40, 3922–3935.
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b) P. Bindu, B. Varghese, M. N. S. Rao, Phosphorus, Sulfur and Sili-
con 2003, 178, 2373–2386.
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Chem. 1984, 23, 1009–1016.
[19] Electronic binding energies are calculated by using the Amsterdam
Density Functional package (ADF2012, SCM, Theoretical Chemis-
Z=4, 1calcd =1.496 gcmÀ3
25.008, 25511 collected reflections, 9896 unique reflections (Rint
0.1147),
,
m=0.777 mmÀ1
,
F
G
=
=
0
restraints, 753 parameters, S=1.062, R1 (I>2s(I))=
0.0919, wR2 (all data)=0.1518, max./min. residual electron density
0.688/À0.522 eꢃÀ3. Selected data for K
U
gcmÀ3, m=0.463 mmÀ1, F
(000)=1044, 2qmax =24.998, 9151 collected
try,
Vrije
Universiteit,
Amsterdam,
The
Netherlands,
reflections, 6693 unique reflections (Rint =0.0603), 331 restraints, 712
parameters, S=1.058, R1 (I>2s(I))=0.0876, wR2 (all data)=
www.scm.com), BLYP/TZ2P with ZORA relativistic corrections;
a) G. te Velde, F. M. Bickelhaupt, S. J. A. van Gisbergen, C. Fonseca
Guerra, E. J. Baerends, J. G. Snijders, T. Ziegler, J. Comput. Chem.
2001, 22, 931–967; b) C. Fonseca Guerra, J. G. Snijders, G. te Velde,
E. J. Baerends, Theor. Chem. Acc. 1998, 99, 391–403.
0.1774, max./min. residual electron density 0.405/À0.386 eꢃÀ3
.
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1992, 114, 1512–1514; b) S. S. Isied, G. Kuo, K. N. Raymond, J. Am.
Chem. Soc. 1976, 98, 1763–1767; c) J. V. McArdle, S. R. Sofen, S. R.
Cooper, K. N. Raymond, Inorg. Chem. 1978, 17, 3075–3078.
[20] Note that these energies are the purely electronic binding energies.
Entropy and solvation effects are not included.
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Am. Chem. Soc. 2009, 131, 12682–12692.
[21] TiACHTUGNTRENNU(G OiPr)4 is used in the experiment, instead of TiCATHUNGTREN(UNNG OMe)4. In our
conceptual model calculations, we ignore this detail for simplicity.
Whereas the absolute energies will be slightly different, the main
points of our reasoning will not be affected by this approximation.
[22] K. N. Raymond, C. Carrano, Acc. Chem. Res. 1979, 12, 183–190.
[16] a) W. R. Harris, K. N. Raymond, J. Am. Chem. Soc. 1979, 101, 6534–
6541; b) W. R. Harris, C. J. Carrano, S. R. Cooper, S. R. Sofen, A. E.
Avdeef, J. V. McArdle, K. N. Raymond, J. Am. Chem. Soc. 1979,
101, 6097–6104; c) L. D. Loomis, K. N. Raymond, Inorg. Chem.
1991, 30, 906–911; d) T. B. Karpishin, T. D. P. Stack, K. N. Raymond,
J. Am. Chem. Soc. 1993, 115, 182–192; e) Z. Hou, T. D. P. Stack,
C. J. Sunderland, K. N. Raymond, Inorg. Chim. Acta. 1997, 263,
Received: May 13, 2013
Published online: July 2, 2013
10542
www.chemeurj.org
ꢂ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2013, 19, 10536 – 10542