Diaminohexopyranosides as ligands in half-sandwich ruthenium(II), rhodium(III), and iridium(III) complexes

Article abstract of DOI:10.1021/om5013117

The syntheses of methyl 2,3-diamino-4,6-O-benzylidene-2,3-dideoxy-α-d-hexopyranosides of glucose, mannose, gulose, and talose and methyl 2-amino-4,6-benzylidene-2,3-dideoxy-3-tosylamido-α-d-glucopyranoside are exhaustively presented, as well as their application as ligands in half-sandwich ruthenium(II), rhodium(III), and iridium(III) complexes. The complex formation occurs highly diastereoselectively, creating a stereogenic metal center. The molecular structures of the ligands and their complexes were investigated by X-ray structure analysis, NMR spectroscopy, polarimetry, and DFT methods. The diamino monosaccharide complexes have been subjected to antitumor activity studies. In vitro tests of a few ruthenium complexes against different cancer cell types showed antiproliferative activities 4-10 times lower than that of cisplatin.

Full text of DOI:10.1021/om5013117

Article
pubs.acs.org/Organometallics
Diaminohexopyranosides as Ligands in Half-Sandwich Ruthenium(II),
Rhodium(III), and Iridium(III) Complexes
Matthias Boge,† Christian Fowelin,† Patrick Bednarski,‡ and Jurgen Heck*,†
̈
̈
†Institute of Inorganic and Applied Chemistry, Department of Chemistry, Hamburg University, Martin-Luther-King-Platz 6, D-20146
Hamburg, Germany
‡Institute of Pharmacy, Ernst-Moritz-Arndt University Greifswald, D-17489 Greifswald, Germany
S
* Supporting Information
ABSTRACT: The syntheses of methyl 2,3-diamino-4,6-O-
benzylidene-2,3-dideoxy-α-D-hexopyranosides of glucose, man-
nose, gulose, and talose and methyl 2-amino-4,6-benzylidene-
2,3-dideoxy-3-tosylamido-α-D-glucopyranoside are exhaustively
presented, as well as their application as ligands in half-
sandwich ruthenium(II), rhodium(III), and iridium(III)
complexes. The complex formation occurs highly diastereose-
lectively, creating a stereogenic metal center. The molecular
structures of the ligands and their complexes were investigated by X-ray structure analysis, NMR spectroscopy, polarimetry, and
DFT methods. The diamino monosaccharide complexes have been subjected to antitumor activity studies. In vitro tests of a few
ruthenium complexes against different cancer cell types showed antiproliferative activities 4−10 times lower than that of cisplatin.
Half-sandwich complexes of ruthenium, rhodium, and
iridium with chelating nitrogen ligands were effectively used
in catalyses such as water oxidation,9a intramolecular hydro-
amination of alkynes,9b Diels−Alder reactions,9c asymmetric
Michael addition reactions,9d asymmetric hydrogenation,9e and
transfer hydrogenation9f,g reactions of ketones and imines.
The first pharmaceutical use of carbohydrate coordination
compounds dates back to the early 20th century. Long before
the discovery of the cytostatic effect of platinum compounds
starting in 1965 by Rosenberg,10a,b aurothioglucose, a polymeric
coordination compound of 1-deoxy-1-thio-β-D-glucose and
gold(I) cations, was prescribed for rheumatism.2a In 1972
Sutton and others synthesized its replacement, auranofin
((2,3,4,6-tetraacetyl-1-deoxy-1-thiolato-β-D-glucose)(triethyl-
phosphane)gold(I)).2b
INTRODUCTION
■
Carbohydrate coordination compounds have been studied for
more than 100 years.1 Early investigations were mainly focused
on pharmaceutical,2a,b physiological,2c−g and technical2h
applications.
However, the first molecular structure of a transition-metal
carbohydrate complex, an alkoxy sugar dimolybdate, was
published in 1981.3a Four years later the first organometallic
transition-metal sugar compound was synthesized, a carbohy-
drate pentacarbonyl manganese complex containing a metal−
carbon σ bond.3b Cyclopentadienyl titanium and zirconium
compounds with alkoxy sugar ligands were investigated with
respect to their application as antitumor agents,4a as chiral
reagents,4b or in catalysis.4c
Transition-metal complexes with ligands derived from amino
sugars have attracted a great deal of interest since 1986.5,6 Ruffo
et al.7a and others7b reported transition-metal complexes of 2,3-
diamino-2,3-dideoxyhexopyranosides and their application in
asymmetric catalysis. Due to their high costs and laborious
preparation, 2,3-diamino-2,3-dideoxyhexopyranosides and their
derivatives were model compounds for analogous oligo- or
polycarbohydrates rather than promising ligands in applied
chemistry. Catalytic studies with chitosane as auxiliary ligand
have demonstrated the large potential of polysaccharides in
asymmetric reactions.8a In 2012 Fontaine et al. published a
modified chitosan with a protecting group in a C6 position and
its use as a polyligand in the synthesis of η6-cymeneruthenium-
(II) complexes. Transfer hydrogenation of acetophenone with
2-propanol and sodium 2-propanolate catalyzed by the
obtained polycomplex yielded (S)-1-phenylethanol with an
enantiomeric excess up to 72%.8b
Twenty years after the ascent of cisplatin10b research on
transition-metal sugar complexes with cytostatic properties was
carried out. In the beginning monoaminocarbohydrate
platinum(II) complexes were synthesized.5a While the first
diamino carbohydrate complex of a transition metal was
reported in 1966 by Guthrie, wherein nickel(II) ions were
chelated by 2,3-diamino-2,3-dideoxyhexopyranosides compara-
ble to the case for ethylenediamine,11a various diamino
carbohydrate complexes analogous to cisplatin and its
derivatives have been synthesized since 1986 which demon-
strated antitumor activity similar to that of platinum(II)
reagents.11b Low toxicity and high selectivity turn diamino
carbohydrate chelating ligands into encouraging auxiliaries in
platinum-containing compounds for medical purposes.
Received: January 2, 2015
Published: April 15, 2015
© 2015 American Chemical Society
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Scheme 1. Synthesis of Methyl 2,3-Diamino-4,6-O-benzylidene-2,3-dideoxy-α-D-glucopyranoside (10) and Methyl 2-Amino-4,6-
a
O-benzylidene-2,3-dideoxy-3-tosylamido-α-D-glucopyranoside (12)
a
Legend: (a) (1) sodium methanolate in methanol, (2) acetic anhydride;16a−c,i,j (b) Amberlite IR120H+ in methanol;16a−c,i,j (c) benzaldehyde
dimethylacetal and tetrafluoridoboric acid in N,N-dimethylformamide;16l (d) methanesulfonyl chloride in pyridine;16a,b,k (e) sodium acetate in 2-
methoxyethanol and water;16a,b,k (f) sodium azide in N,N-dimethylformamide and 1,4-dioxane;16a,b,k (g) normal atmospheric pressure of H2 and
Pd(C) in methanol;16a,b,k (h) potassium hydroxide in ethanol;16c (i) p-tosyl chloride in dichloromethane and pyridine.
Trigonal platinum(0) complexes with carbohydrate-derived
diimine ligands were reported with respect to antitumor
application.5b Yano and Mikata linked pyranosides to diamine
ligands chelating platinum(II). Their idea was to create
antitumor reagents which are more specific toward cancer
cells utilizing the faster metabolism and, thus, greater
carbohydrate uptake of the degenerated cells. The new sugar
complexes could compete with cisplatin in in vitro tests.11c
η5-cyclopentadienylrhodium(III), -iridium(III), and η6-
areneruthenium(II) complexes. Furthermore, we will present
results from antiproliferative studies of the carbohydrate
complexes with different cancer cell types. In further
publications the novel complexes will be applied as precatalysts
in catalytic hydrogenation reactions.
RESULTS AND DISCUSSION
■
Moker and Thiem reported similar cis-diamminemalonato-
̈
Synthesis of the Hexopyranoside Ligands. The syn-
thesis of 2,3-diamino-2,3-dideoxy-D-glucopyranosides has al-
ready been reported.16a−h The introduction of the benzylidene
protecting group yielding 4 was carried out by means of
tetrafluoridoboric acid. This procedure was also applied in the
synthesis of 20.16l Tosylation of 9 and subsequent cleavage of
the acetyl amido group led to the formerly unknown methyl 2-
amino-4,6-O-benzylidene-2,3-dideoxy-3-tosylamido-α-D-gluco-
pyranoside (12; Scheme 1).
platinum(II) complexes linked to D-glucose in 2009. The
antitumor activity of these compounds was comparable to that
of carboplatin.11d
A galactal complex of a hydridocarbonylruthenium cluster
showed high activity against chronic myelogical leukemia and
other types of cancer cells comparable to the effects of
cisplatin.12 Currently, pentamethyl-η5-cyclopentadienyliridium-
(III) and -rhodium(III),13a−c η6-areneruthenium(II) half-
sandwich,13d−g and octahedral iridium(III),14 rhodium(III),14
and ruthenium(II)15 complexes are the focus of antitumor
research, with the objective that other metals might tackle the
cancer cells, as the cis-Pt complexes are becoming too inactive.
Another aspect is the search for less toxic complexes.13a
With this publication we wish to describe the synthesis and
molecular structure of methyl 2,3-diamino-4,6-O-benzylidene-
2,3-dideoxy-α-D-hexopyranoside ligands and their pentamethyl-
The synthesis of 2,3-diamino-2,3-dideoxy-D-manno-pyrano-
sides has been reported as well,16h,m−p though not in as detailed
and coherent a manner as for the 2,3-diamino-2,3-dideoxy-D-
glucopyranosides. For example, there is no detailed description
for the subsequent reduction of the azide functions to amino
groups. Guthrie used a hydrogenation reaction with Adams’
catalyst,16n,o while Ruffo and co-workers applied the Staudinger
reaction pathway.5c The subsequent reduction of both azide
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a
Scheme 2. Synthesis of Methyl 2,3-Diamino-4,6-O-benzylidene-2,3-dideoxy-α-D-mannopyranoside (19)
a
Legend: (a) methanesulfonyl chloride in pyridine;16n,o,q (b) sodium methanolate in methanol;16n,o,q (c) sodium azide and ammonium chloride in 2-
methoxyethanol and water;16n,o (d) p-tosyl chloride and 4-(N,N-dimethylamino)pyridine in dichloromethane and pyridine;16r (e) sodium azide in
N,N-dimethylformamide and 1,4-dioxane; (f) lithium alanate in tetrahydrofuran.
Scheme 3. Synthesis of Methyl 2,3-Diamino-4,6-O-benzylidene-2,3-dideoxy-α-D-gulopyranoside (29) and Methyl 2,3-Diamino-
a
4,6-O-benzylidene-2,3-dideoxy-α-D-talopyranoside (32)
a
Legend: (a) benzaldehyde dimethylacetal and tetrafluoridoboric acid in N,N-dimethylformamide;16l (b) methanesulfonyl chloride in pyridine; (c)
16qsodium methanolate in methanol; (d) sodium azide and ammonium chloride in 2-methoxyethanol and water;16u (e) triflic anhydride and 4-(N,N-
dimethylamino)pyridine in dichloromethane and pyridine; (f) trimethylsilyl azide and tetra-n-butylammonium fluoride in tetrahydrofuran; (g)
lithium alanate in tetrahydrofuran; (h) p-trifluoromethanebenzenesulfonyl chloride and 4-(N,N-dimethylamino)pyridine in dichloromethane and
pyridine
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groups by means of lithium alanate was demonstrated to be the
most efficient procedure for the syntheses of 19 (Scheme 2)
and of 29 and 32 (Scheme 3). The formation of 2,3-diamino-
2,3-dideoxy-D-gulopyranosides16e has been reported similarly to
the synthesis outlined here, but the methyl D-gulopyranoside
was merely characterized as its diacetylamide, as was the case
for all of the 2,3-diamino-2,3-dideoxy-D-hexopyranosides before
1986. Moreover, 2,3-diamino-2,3-dideoxy-D-talopyranosides
have yet been entirely prepared on the basis of a strategy
involving nitro monosaccharides.16t
N3. When the dihedral angle δ includes two equatorially
arranged amino groups (Chart 1a) or one equatorially and one
axially arranged amino group (Chart 1b), δ roughly amounts to
60°, whereas δ is close to 180° (Chart 1c) when the planes
include two axially arranged amino groups, which then are not
suitable for a chelating coordination. For that purpose
carbohydrate ligands with amino substituents in orientation
(a) such as glucose (or galactose) and (b) such as mannose or
talose were prepared. A similar orientation of the substituents is
given in gulose (and allose), where both amino groups are
inverted in comparison to the arrangement in Chart 1b. Thus, a
ligand with a gulose backbone was also synthesized. Closely
related to the dihedral angle is the nonbonding N2,N3 distance
d.
The anhydroguloside 23 and the anhydrotaloside 24,
respectively, were converted to the 2-azidoidopyranoside 25
and the 3-azidoidopyranoside 26, respectively.16u The mixture
was separated by chromatographic methods.
Esterification of 26 with triflic anhydride gave the sulfonate
27, which was converted to the 2,3-diazidogulopyranoside 28
by means of trimethylsilyl azide and tetra-n-butylammonium
fluoride. Common leaving groups were not suitable for the
inversion of 25 at the C3 position. Thus, 25 was esterificated
with p-trifluoromethanebenzenesulfonyl chloride, producing
sulfonate 30, which was not fully characterized. Substitution
of the sulfonate with trimethylsilyl azide and tetra-n-
butylammonium fluoride yielded the 2,3-diazidotalopyranoside
31.
Unfortunately, suitable crystals for an X-ray structure
determination could only be obtained for 2,3-diazidomanno-
pyranoside 18 and 2,3-diazidotalopyranoside 31 (molecular
structures are given in Figure S1.1 and crystallographic data in
Table S1.1 in the Supporting Information). Therefore, the
molecular structures of the diaminopyranosides 10, 19, 29, and
32 as well as those of the diazidopyranosides 18, 28, and 31
were calculated by DFT methods17 (Table 1). The reliability of
the molecular structures calculated by DFT methods can be
evaluated by comparison of the molecular structures obtained
by means of X-ray structure determination as well as DFT
calculations for 18 and 31.
For compounds 18 and 31 the N2,N3 distances d obtained
from X-ray structure analysis correspond with those derived
from DFT calculations, while the dihedral angle δ differs
significantly by about 10°, which may be due to interactions in
the crystal packing. Overall the structural data derived from
DFT calculations (of both functionals BP86 and B3LYP)
correlate well with those from single-crystal X-ray structure
analysis. Hence, structural data originating from DFT
calculations using the hybrid functional B3LYP was used to
draw the molecular structures of 10, 19, 28, 29, and 32 (Figure
S5.1 in the Supporting Information).
Chart 1. Dihedral Angles (δ) Defined by the Planes N2−
C2−C3 and C2−C3−N3 and Distances (d) between Two
Equatorially Arranged (a), One Equatorially and One Axially
Arranged (b), and Two Axially Arranged Amino Groups (c)
in 2,3-Diamino-2,3-dideoxy-D-hexopyranosides
The dihedral angle δ of compound 10 (gluco) was calculated
to be 62.6° (B3LYP). The corresponding dihedral angles of 19
(manno), 29 (gulo) and 32 (talo) were calculated to be 50.1,
49.8, and 53.4°, respectively. The N2,N3 distances d of the 2,3-
diaminopyranosides increase with an increasing number of
axially arranged substituents in the order 288 pm (10), 291 pm
(19), 293 pm (29), and 295 pm (32).
Structural Discussion of Methyl 2,3-Diamino-4,6-O-
benzylidene-2,3-dideoxy-α-D-hexopyranosides. The ca-
pability of the chelating coordination mode of the four 2,3-
diamino-2,3-dideoxy-D-hexopyranosides depends on the dihe-
dral angle δ defined by the planes N2−C2−C3 and C2−C3−
Table 1. Dihedral Angles δ and Nonbonding N2,N3 Distance d in Methyl 2,3-Diamino- (10, 19, 29, 32) and 2,3-Diazido-2,3-
dideoxy-D-hexopyranosides (18, 28, 31) Derived from X-ray Structure Determinations and DFT Calculations
selected structural data obtained from
a
a
X-ray structure analysis
DFT calculation (functional BP86)
DFT calculation (functional B3LYP)
b
b
b
compound
δ (deg)
d (pm)
δ (deg)
d (pm)
δ (deg)
d (pm)
10 (gluco)
18 (manno)
19 (manno)
28 (gulo)
29 (gulo)
31 (talo)
62.3
46.4
49.6
61.3
49.7
54.1
53.3
287
62.6
45.8
50.1
60.6
49.8
53.6
53.4
288
c
c
c
c
56.07(22)
63.68(22)
283.3(3)
284
284
290
291
c
c
297
295
293
293
c
c
299.0(3)
301
300
32 (talo)
296
295
a
Structural data obtained by calculations using DFT methods from Orca 2.9, functionals BP86 and B3LYP, and basis sets TZV for H and
TZV(2d2p) for main-group elements.17 Dihedral angle δ defined by the planes N2−C2−C3 and C2−C3−N3. Distances d between N2 at C2 and
N3 at C3.
b
c
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For compounds 10, 19, and 32 the single-point energies of
the optimized structures with constrained dihedral angles δ
were calculated for 10−15° from optimum (Figure 1). The
ability of the two amino groups to adopt a chelating
coordination mode at different metal centers was examined:
for all ligands (10, 19 and 32) low energy barriers of about 3
kJ/mol were calculated for the deviations of the dihedral angles
10° from optimum. With deviations of 5° the energy barrier
even decreased to 1 kJ/mol (Table 2).
Hence, the DFT calculations confirmed a certain flexibility of
the amino functions of the 2,3-diaminohexopyranosides, which
makes them capable to chelate metal atoms of different sizes, as
long as the metal atoms are not extraordinarily small (as Ti4+
cations)18a or large (as Hg2+ cations).18b Therefore, an easy
coordination of middle and late transition metals can be
expected, and it is not surprising that coordination compounds
of the metals with cis-coordinated 1,2-disubstituted ethylenedi-
amine-type ligands (N,N-en-type ligands) (Table 3) possess
dihedral angles defined by the planes N1−C1−C2 and C1−
C2−N2 comparable to those of ligands 10, 19, 29, and 32
(Table 1).18c−g
Synthesis and Structure of the Half-Sandwich
Ruthenium, Rhodium, and Iridium Complexes. The first
monomeric η5-cyclopentadienylrhodium(III) and -iridium(III)
and η6-areneruthenium(II) complexes were reported by Maitlis
et al.19a,b in 1969 and Zelonka and Baird19c,d in 1972,
respectively. With the dimeric species [{M(ArH)Cl}2-(μ-
Cl)2] (33a, M = Ir, ArH = Cp*; 33b:, M = Rh, ArH = Cp*;
33c, M = Ru: ArH = benzene; 33d, M = Ru, ArH = p-cymene;
33e, M = Ru, ArH = tetralin) as starting material, the
monomeric compounds were obtained by addition of the
chelating ligand and substitution of one chlorido ligand per
metal center.19e Hence, silver or ammonium salts were used,
depending on the solubility of the resulting complex.
Complexes with high solubility were favorably prepared in
dichloromethane with silver salts,19f whereas complexes with
low solubility were synthesized in methanol with ammonium
salts (Scheme 4).19g
Thus, the iridium(III) complex 34 with ligand 10 (gluco)
and rhodium(III) complexes 35, 39, 42, 43, and 46 and
ruthenium(II) complexes 36-38, 40, 41, 44, 45, 47, and 48
were synthesized (Scheme 4).
Compounds 34−48 were fully characterized by NMR
spectroscopy, elemental analysis, polarization angle, and (if
needed) high-resolution mass spectrometry. Compounds 34,
35, 39, 42, and 46 were crystallized, and their molecular
structures were determined by X-ray crystallography. The
complexes demonstrate the expected structures. The absolute
configuration at the metal centers of 34, 35 (gluco), and 46
(talo) is T-4-S, while the configuration of 42 (gulo) is T-4-R,
when the geometries of these piano-stool complexes are
considered as (pseudo)tetrahedral (Figure 2; stereodescriptor
[T-4-R/S] with T-4 denoting tetrahedral and R/S absolute
configuration following the CIP rules). The configurations at
the metal centers in the solid-state structures are in accordance
with the configuration in liquid solution identified by the NMR
Figure 1. DFT calculated energy barriers (final single-point energy) of
the dihedral angles δ of methyl 2,3-diamino-4,6-O-benzylidene-2,3-
dideoxy-α-D-glucopyranoside (10), methyl 2,3-diamino-4,6-O-benzyli-
dene-2,3-dideoxy-α-D-mannopyranoside (19), and methyl 2,3-diami-
no-4,6-O-benzylidene-2,3-dideoxy-α-D-talopyranoside (32) (Orca 2.9,
functionals BP86 and B3LYP, basis sets TZV for H and TZV(2d2p)
for main-group elements).17
Table 2. Energy Barriers (kJ/mol) for the Deviations from the Optimal Dihedral Angles δ Calculated by DFT Methods
deviation
−10°
−5°
+5°
+10°
compound
BP86
B3LYP
BP86
B3LYP
BP86
B3LYP
BP86
B3LYP
10 (gluco)
19 (manno)
32 (talo)
3.4
2.9
2.5
3.6
3.4
2.9
0.9
0.8
0.7
1.0
1.1
0.8
0.8
0.8
0.7
0.8
0.7
0.8
3.2
3.2
2.5
3.2
2.9
2.9
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Table 3. Dihedral Angles Defined by the Planes N1−C1−C2 und C1−C2−N2 of Transition Metals with Cis-Coordinated N,N-
en-Type Ligands and Chlorido Ligands
metal center
cis-N,N ligand
dihedral angle (planes N1−C1−C2 and C1−C2−N2) (deg)
a
b
Ru2+
cis,cis-dach
48.71(56)18c
51.55(6)18d
50.87(60)18e
49.57(113)18f,g
b
Pt2+
Pt2+
Pt2+
cis,trans-dach
b
cis,cis-dach
methyl 2,3-diamino-2,3-dideoxy-α-D-mannopyranoside
a
b
1,4-Bis(diphenylphosphino)butane (dppb) as an additional neutral ligand. dach: 1,2-diaminocyclohexane.
Scheme 4. Synthesis of Compounds 34−48
spectra of complexes 34−38 with ligand 10 (gluco), complexes
42−45 with ligand 29 (gulo), and complexes 46−48 with
ligand 32 (talo), which reveal only one diastereomer for each
compound in dichloromethane at room temperature. The
asymmetric unit of 34 and 35 contains one molecule of diethyl
ether per two cationic complexes, which was treated as a diffuse
contribution to the total electron density. Crystals of 42 contain
acetone and those of 46 dichloromethane, but their structures
were solved including the solvent molecules. All compounds
except for 39 crystallize in the space group P212121 with R1 =
0.0513 (34), 0.0556 (35), 0.0560 (42), 0.0292 (46). The
mannopyranoside complex 39 was found as a diastereomeric
mixture with a ratio of roughly 1:1 for T-4-R/T-4-S in liquid
solution (dichloromethane) at room temperature. However,
the molecular structure in the solid state demonstrates the
configuration T-4-R (R1 = 0.0379). A crystal for the molecular
structure determination of 39 was obtained from a chloride-
containing batch, and the compound crystallized with a mixture
of the anions tetrafluoridoborate and chloride in the ratio 2:1.
The space group is P21, and the asymmetric unit contains one
molecule of water and three cationic complexes. Partially
cocrystallized dichloromethane was treated as a diffuse
contribution to the total electron density of the data sets
(crystallographic data in Table S1.2 in the Supporting
Information).
Supporting Information). For the crystal structures of 35
(ligand 10, gluco) and 39 (ligand 19, manno) an intermolecular
face-to-face stacking mode of the aromatic Cp* ligand of one
cationic complex and the phenyl group of the neighboring
complex is observed, which is displaced slightly parallel (the
intermolecular distances between related carbon atoms are
about 360 pm). This stacking feature is responsible for the
pillard alignment of the complexes in the crystalline state of 35
and 39 (Figure S1.2). A column stacking mode of the
complexes in the crystalline state is also observed for
compound 42 (ligand 29, gulo), but in contrast to the case
for 35 and 39 the column structure in 42 is the result of an
intermolecular edge-to-face order of the methyl hydrogen
atoms of the Cp* ligand of one complex and the aromatic plane
of the phenyl group of the next molecule (Figure S1.2; the
intermolecular distances between related carbon atoms are
about 360 pm).
The structures of complexes 35, 39, and 42 are different from
that of 46 (ligand 32, talo), where an intramolecular attractive
edge-to-face interaction is located between the phenyl ring of
the sugar ligand and the Cp* ring of the same complex (the
distances between the nearest methyl carbon atom of the Cp*
ring and the phenyl carbon atoms are estimated to be about
350 pm). In addition, the back side of the phenyl ring of one
complex is arranged in an intermolecular face-to-face mode to
the next complex displaced in a slightly parallel manner. The
distances of related carbon atoms of the two rings are about
340−400 pm. This creates a staircaselike arrangement of the
interacting complexes in the crystal (Figure S1.2 in the
Supporting Information). All measured distances are in
accordance with the distances assumed for π interactions.21
Similarly to 39 the mannopyranoside complexes 40 and 41
were obtained as diastereomeric mixtures in the ratio [T-4-R]:
[T-4-S] 1:3 for 40 and [T-4-R]:[T-4-S] 1:2 for 41. The
assignment of the NMR signals of the [T-4-R] and [T-4-S]
diastereomers of 39 and 40 (Figure 3) was accomplished by
comparison of the NMR spectra and the calculated molecular
The experimentally determined bond lengths between the
metals and the chlorido ligands as well as the nitrogen atoms of
the carbohydrate ligands in 34, 35, 39, 42, and 46 are in quite
good accordance with the molecular structure optimization by
DFT17 calculations for these compounds. The bond lengths
between ligand atoms and the iridium atom in 34 are
insignificantly larger than the bond lengths between ligand
atoms and the rhodium atom in 35 (Table 4). This is not
unexpected, since the ionic radius of Ir(III) is very much the
same as that for Rh(III).20
The crystal structures of 35, 39, 42, and 46 indicate intra-
and intermolecular attractive interactions (Figure S1.2 in the
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Figure 2. Molecular structures of 34 (P212121, R1 = 0.0513), 35 (P212121, R1 = 0.0556), 39 (P21, R1 = 0.0379), 42 (P212121, R1 = 0.0560), and 46
(P212121, R1 = 0.0292) derived from X-ray structure determination. The complexes are positively charged. Hydrogen atoms, cocrystallized solvent
molecules, and counterions are omitted for clarity.
structures of the diastereomers. The protons of the alkyl groups
of the arene ligands are facing the sugar ligand protons. Thus,
the diastereomers are identified by through-space coupling of
the arene protons with the particular ligand protons (NOE
contacts in Figure 3). The similarity of their proton NMR
spectra implies the same assignment of the proton signals for
40 and 41, respectively.
The specific polarization angles of compounds 34−38 and
42−48 were measured (Table 5). Compounds 39−41 (ligand
19) are diastereomeric mixtures (T-4-R and T-4-S config-
uration); thus, their polarization angles are omitted.
The similarity of the polarization angles of 34−38 (ligand
10) leads to the conclusion that these complexes adopt the
same configuration at the metal atom in liquid solution at room
temperature. The absolute configuration of compound 37 was
confirmed as T-4-S in liquid solution by NMR spectra (Figure
3) and was the same as that obtained from X-ray structure
determinations for 34 and 35.
For the complexes 46−48 (ligand 32) the T-4-S config-
uration is stabilized by the intramolecular attractive edge-to-face
interactions between the protons of the arene ligand and the
phenyl ring of the sugar ligand, in agreement with the DFT
calculations of 46. In this edge-to-face arrangement the Cp*
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Table 4. Dihedral Angles δ, Nonbonding N2,N3 Distances d, and Selected Bond Lengths of 34 (Ir), 35 (Rh), 39 (Rh), 42 (Rh),
and 46 (Rh) Derived from X-ray Structure Determination and Corresponding DFT Optimized Structures17
bond length (pm; M = Ir/Rh)
a
b
compound
δ
(deg)
d
(pm)
M−N2
M−N3
M−Cl
[T-4-S]-34 (Ir, gluco)
59.88(78)
273.5(10)
273.7(11)
274.80(41)
275.28(74)
279 (DFT)
279 (DFT)
272.4(3)
217.0(7)
216.4(7)
241.2(2)
58.23(90)
216.0(8)
215.8(7)
241.4(2)
[T-4-S]-35 (Rh, gluco)
56.27(32)
214.5(3)
214.3(3)
241.65(10)
241.76(10)
242 (DFT)
241 (DFT)
241.97(6)
242.27(7)
239.36(7))
241 (DFT)
242 (DFT)
244.4(1)
58.83(42)
214.7(4)
213.2(3)
c
[T-4-R]-35 (Rh, gluco)
57.4 (DFT)
56.7 (DFT)
50.14(24)
220 (DFT)
219 (DFT)
216.1(2)
218 (DFT)
219 (DFT)
215.46(19)
215.4(2)
c
[T-4-S]-35 (Rh, gluco)
[T-4-R]-39 (Rh, manno)
46.73(25)
272.49(30)
273.98(26)
277 (DFT)
279 (DFT)
275.8(6)
215.9(2)
49.77(25)
215.2(2)
214.5(2)
c
[T-4-R]-39 (Rh, manno)
48.7 (DFT)
53.4 (DFT)
44.21(50)
218 (DFT)
220 (DFT)
216.0(4)
219 (DFT)
218 (DFT)
213.5(4)
c
[T-4-S]-39 (Rh, manno)
[T-4-R]-42 (Rh, gulo)
c
[T-4-R]-42 (Rh, gulo)
50.2 (DFT)
41.5 (DFT)
45.35(14)
277 (DFT)
268 (DFT)
272.53(17)
268 (DFT)
221 (DFT)
221 (DFT)
216.87(12)
218 (DFT)
219 (DFT)
220 (DFT)
218 (DFT)
214.3(3)
240 (DFT)
240 (DFT)
242.30(3)
239 (DFT)
242 (DFT)
c
[T-4-S]-42 (Rh, gulo)
[T-4-S]-46 (Rh, talo)
c
[T-4-R]-46 (Rh, talo)
43.1 (DFT)
49.9 (DFT)
222 (DFT)
222 (DFT)
c
[T-4-S]-46 (Rh, talo)
276 (DFT)
a
b
c
Dihedral angle defined by the planes N2−C2−C3 and C2−C3−N3. Nonbonding N2,N3 distance. Structural data obtained by calculation using
DFT methods by Orca 2.8, functional BP86, and basis sets TZV for H, TZV(2d2p) for main-group elements, and TZV(2d2fg,3p2df) for transition
elements.17
Figure 3. DFT calculated molecular structures of [T-4-S]-37, [T-4-R]-39, [T-4-S]-39, [T-4-R]-40, and [T-4-S]-40 with observed NOE contacts (see
arrows) (Orca 2.8, functionals BP86 and DefBas-4, basis sets TZV for H, TZV(2d2p) for main group elements, and TZV(2d2fg,3p2df) for transition
elements).17 The complexes are positively charged. Hydrogen atoms, except for those which demonstrate NOE effects, and counterions are omitted
for clarity.
protons are located in the shielding area of the benzene ring,
which shifts the signals of the protons of the Cp* ligand to high
field (see 46).22 In contrast, 42 (ligand 29) should have the
absolute configuration T-4-R, which was confirmed for the
related complex 45 in solution by NOE contacts between the
methoxy group of the sugar ligand and the protons of the
substituents of the arene ligand. As expected for this
configuration, the proton NMR signals of the phenyl ring of
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final step of the ligand synthesis.24 In the case of chemically
unequal amino groups the p-toluenesulfonylation reaction
could not be conclusively executed with regard to the formation
of regioisomers. Therefore, methyl 2-amino-4,6-O-benzylidene-
2,3-dideoxy-3-N-p-toluenesulfonylamido-α-D-glucopyranoside
(12) was synthesized from 9. Two complexes were produced
on the basis of ligand 12 (Scheme 5): dichlorido-η1-(methyl 2-
589 nm
Table 5. Specific Polarization Angles ([α]
Cationic Complexes 34−38 and 42−48
(deg)) of the
25 °C
polarization
angle
(deg) (solvent)
transition
metal
arene
a
compound [absolute configuration]
ligand
methyl 4,6-O-benzylidene-α-D-
+110.4
d
23a
,
glucopyranoside
(tcm)
benzyl 2,3-diamino-4,6-O-
benzylidene-2,3-dideoxy-α-D-
glucopyranoside
+95
(MeOH)16a,b
Scheme 5. Synthesis of Compounds 51 and 52
b
e
34 [T-4-S]
Ir(III)
Rh(III)
Ru(II)
Ru(II)
Ru(II)
Cp*
Cp*
C6H6
Cy
−51 (dcm)
−37 (dcm)
−43 (dcm)
−48 (dcm)
b
e
35 [T-4-S]
b
e
36 [T-4-S]
b
e
37 [T-4-S]
b
e
38 [T-4-S]
Tet
−74 (dcm)
d
23b
,
methyl 4,6-O-benzylidene-α-D-
+79.8 (tcm)
gulopyranoside
e
29
+85 (dcm)
b
42 [T-4-R]
Rh(III)
Rh(III)
Rh(III)
Ru(II)
Ru(II)
Ru(II)
Cp*
Cp*
Cp*
Cy
+135 (acetone)
+75 (acetone)
c
43 [T-4-R]
c
e
43 [T-4-R]
+135 (dcm)
b
e
44 [T-4-R]
+106 (dcm)
b
44 [T-4-R]
Cy
+114 (acetone)
+133 (acetone)
c
45 [T-4-R]
Tet
amino-4,6-O-benzylidene-2,3-dideoxy-3-p-tosylamido-α-D-glu-
copyranoside)-η6-(1′,2′,3′,4′-tetrahydronaphthalene)-
ruthenium(II) (51) and dichlorido-η1-(methyl 2-amino-4,6-O-
benzylidene-2,3-dideoxy-3-p-tosylamido-α-D-glucopyranoside)-
pentamethyl-η5-cyclopentadienylrhodium(III) (52).
d
,
23c
methyl 4,6-O-benzylidene-α-D-
+80.4 (tcm)
talopyranoside
e
e
e
e
32
+82 (dcm)
+56 (dcm)
+56 (dcm)
+52 (dcm)
b
46 [T-4-S]
Rh(III)
Ru(II)
Ru(II)
Cp*
Cy
b
47 [T-4-S]
Compounds 51 and 52 were obtained by stirring the ligand
and complex precursor in dichloromethane (Scheme 5). The
ligand binds to the metal by the amino group at C2. A chelating
coordination might be achieved by deprotonation of the p-
tosylamido group at C3. However, under basic conditions
(sodium methanolate, triethylamine) degradation of the ligand
took place. Therefore, only the η1 complexes were obtained.
The complexes were characterized by NMR spectroscopy,
elemental analysis, polarization angle, and mass spectrometry.
Antitumor Activity Studies. Due to the recent results with
iridium(III), rhodium(III), and ruthenium(II) half-sandwich
complexes in antitumor applications,13 the effect of the novel
complexes 34−48 on three cancer cell lines was tested. In
contrast to complexes with conventional organic ligands sugar
complexes might provide less toxicity while preserving the
cytostatic activity of related complexes. Metabolic interaction of
the sugar ligand could increase the specificity of the complexes
toward cancer cells. Thus, an antitumor agent with a higher
therapeutic index might be obtained.
The cytotoxicity testing with the three adherent cell lines was
carried out by an antiproliferation assay based on the staining of
cells with crystal violet, following a method that was described
earlier.25a,b The adherent cell lines originated from cervical
(SISO), pancreas (DAN-G), and lung (LCLC-103H) cancers.
In primary screening (see Table S4 in the Supporting
Information) the T/C values of complexes 34 and 37 (ligand
10, gluco), 40 and 41 (ligand 19, manno), 44−46 (ligand 29,
gulo), and 46−48 (ligand 32, talo) were examined. Of all of
these complexes the Ru derivatives 40, 41, and 48 displayed the
most promising T/C values.
b
48 [T-4-S]
Tet
a
Cp* = pentamethyl-η5-cyclopentadienyl, C6H6 = η6-benzene, Cy =
b
η6-p-cymene, Tet = η6-tetralin. Counterion tetrafluoridoborate.
c
d
e
Counterion hexafluoridophosphate. tcm = trichloromethane. dcm
= dichloromethane.
the sugar ligand are poorly separated due to the distal position
of the phenyl ring relative to the arene ligand. Unfortunately,
the determination of the polarization angles is hampered by the
insufficient solubility of complexes 42−45 with the ligand 29
(gulo). Therefore, data from those analytes suffer from large
errors, which may explain the high variance of the measured
values from measurements in different solvents. The methyl
4,6-O-benzylidene-α-D-pyranosides23 and benzyl16a,b or methyl
2,3-diamino-4,6-O-benzylidene-α-D-pyranosides of each sugar
backbone show polarization angles similar to those demon-
strated for the gluco-, gulo-, and talopyranosides.
Though the complexes of ligands 29 (gulo) and 32 (talo)
illustrate polarization angles similar to those of their diamino
pyranoside congeners, a large difference is observed between
the polarization angles of α-D-glucopyranosides and those for
the complexes of the corresponding diaminoglucopyranoside
10. However, the T-4-S configuration seems to have a tendency
for a negative shift in the polarization angle while the
polarization angles of 42−45 (T-4-R) are somewhat larger
than those of the gulopyranosides. Hence, the configuration T-
4-R has a tendency for a positive shift in the polarization angle,
which is opposite to the effect of T-4-S, as expected.
Final Synthetic Strategy Regarding the Grade of
Inequivalence of the Binding Groups of the Ligands.
The synthesized ligands and complexes were designated as
precursors in Noyori-type transfer hydrogenation. However,
the usual concept, to prevent two identical active sides in the
catalyst, is to discriminate the (two) amino groups. This is
usually achieved by sulfonylation of one amino group in the
Therefore, these three Ru(II) compounds were tested in a
secondary screening, wherein their IC50 values were determined
(Table 6). This demonstrated that especially η6-tetralin
ruthenium complex 41 with the mannopyranoside ligand 19
has antiproliferative activity against the cell lines SISO and
LCLC-103H that is 4−10 times lower than that of cisplatin.25d
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70 eV (EI-MS) and a Agilent Technologies 6224 TOF LC-MS
instrument (ESI-HRMS). UV/vis spectra were recorded in dichloro-
methane on a Varian Cary 5E UV/vis-NIR spectrometer. Polarization
Table 6. Secondary Screening of Selected Substances: IC50
Values
a
b
IC50 (μM, am ) ( sd )
angles were measured with an A. Kruss Optronic GmbH P8000T
̈
polarimeter. The specific polarization angles were determined by
known methods.26g Column chromatography was performed on silica
gel 60 (70−230 mesh) from Merck and Macherey & Nagel. All
chemical reagents were purchased from commercial sources and used
as received (for example μ-dichloridobis[chloridopentamethyl-η5-
cyclopentadienyliridium(III)] (33a) from Acros; 99%) unless other-
wise indicated, except for 4-trifluoromethylbenzenesulfonyl chlor-
ide,26h,i μ-dichlorido-bis[chlorido-pentamethyl-η5-cyclopentadienyl-
rhodium(III)] (33b),19a,b μ-dichloridobis[chlorido-η6-benzene-
ruthenium(II)] (33c),19c μ-dichloridobis[chlorido-η6-p-
cymeneruthenium(II)] (33d),26j and μ-dichloridobis[chlorido-η6-
(1,2,3,4-tetrahydronaphthalene)ruthenium(II)] (33e),26k which were
synthesized by literature procedures. The synthesis of the organic
compounds is described in the Supporting Information (section S2).
DFT Studies. Orca 2.8 and 2.917a were used for DFT calculations.
The functional BP8617b and the hybrid functional B3LYP13c were
applied for structure optimization of the organic structures with
DefBas-3 basis sets (basis sets: H, Ahlrichs-TZV; main-group
elements, Ahlrichs-TZV(2d2p)).17d,e For structure optimization of
the organometallic complexes the functional BP8617b with DefBas-4
basis sets (basis sets: H, Ahlrichs-TZV; main-group elements, Ahlrichs-
TZV(2d2p); second-row transition elements, Ahlrichs-TZV-
(2d2fg,3p2df))17d−f was used. Usually some constraints were used
for optimization such as (commands) TightOpt, SlowConv, Grid4,
NoFinalGrid, and Decontract, and when problems with negative
frequencies arose, additional constraints were added as needed such as
(commands) Grid6, Grid7, TightSCF, VerySlowConv, VerytightSCF,
and ExtremeSCF. All minima were verified to have no negative
frequencies (under −50 cm−1). For optimization of crowded
organometallic structures a van der Waals correction (VDW06) was
used.17g In the case of compounds 10, 19, and 32 single-point energies
were calculated for optimized structures with constraint dihedral
angles defined by the planes N2−C2−C3 and C2−C3−N3 for
examination of the progress of the potential for deviating dihedral
angles (from the minimum structure). The explanation of the used
commands is given in the user manual of Orca 2.9 (OrcaManual
2.9).17h The resulting xyz files, free energies, and single-point energies
as well as the command files are deposited in the Supporting
Information (S5).
compound
DAN-G
SISO
LCLC-103H
c
d
d
40 (Ru, manno)
41 (Ru, manno)
48 (Ru, talo)
26.9
5.54(1.95)
12.5(2.8)
d
f
d
d
28.5(13.9)
2.79(0.31)
4.39(3.20)
e
d
c
-
32.5(32.8)
20.2
f
f
f
cisplatin
0.53(0.07)
0.24(0.05)
1.1(0.4)
a
b
c
Arithmetic mean. Standard deviation from three assays. From two
d
e
f
assays. From three assays. Not determined. From ref 25d.
CONCLUSION AND OUTLOOK
■
One amino-tosylamido- and four diaminocarbohydrate ligands
were synthesized and characterized. DFT calculations indicate a
considerable flexibility of the dihedral angle of the diamino
ligands, which makes the amino functions capable of chelating
most transition metals. These ligands will be applied in further
transition-metal complexes, which is beyond the scope of this
publication.
With these ligands the synthesis of the half-sandwich
ruthenium(II), rhodium(III), and iridium(III) diamino sugar
complexes was feasible. The structures of these 17 new
complexes, including their configuration at the metal center,
were determined in the crystalline phase by X-ray crystallog-
raphy and in liquid solution by NMR spectroscopy and
polarimetry. The pseudotetrahedral complexes formed with
high diastereoselectivity, illustrating a stereogenic metal atom:
with the gluco- and talopyranoses 10 and 32, respectively, a T-
4-S configuration, for the gulopyranose 29 a T-4-R config-
uration, and for complexes with the mannopyranose ligand 19
diastereomeric mixtures are obtained. The origin of the
diastereoselectivity of the complex formation will be examined
by epimerization studies and further DFT calculations.
Moreover, the new half-sandwich ruthenium, rhodium, and
iridium diamino sugar complexes will be applied as catalyst
precursors in Noyori-type transfer hydrogenation.
The antiproliferative properties of the majority of the new
complexes were examined. Compounds 40 and 41 show IC
values 4−10 times larger than those of cisplatin toward different
cancer cell types.
X-ray Crystallographic Studies. Colorless crystals were grown
from 18, 25, 26, and 31 by evaporation of the solvent at normal
pressure and room temperature from a mixture of trichloromethane, n-
hexane, and petroleum. Yellow and orange-yellow crystals were
obtained from 34, 35, 39, 42, and 46 by recrystallization from
dichloromethane and diethyl ether at −20 °C and in the case of 42 by
recrystallization from acetone and n-heptane (room temperature). The
X-ray single-crystal structures were determined on a Bruker SMART
CCD diffractometer with Mo Kα radiation (λ = 71.073 pm); programs
used SAINT,26l SADABS,26m XPREP,26n SHELXS-97,26o SHELXL-
EXPERIMENTAL SECTION
■
General Considerations. All the manipulations of air-sensitive
compounds were carried out under a nitrogen atmosphere using the
standard Schlenk techniques.26a The solvents were dried and distilled
prior to use by literature methods.26b,c 1H and 13C NMR spectra
(DEPTQ/APT) were recorded on a Bruker Fourier 300 (1H, 300
MHz; 13C, 75 MHz) and/or on a Bruker Avance 400 (1H, 400 MHz;
13C, 100 MHz) at room temperature, and the chemical shift values
refer to acetone-d6 (δ(1H), 2.05 ppm; δ(13C), 29.84 ppm),26d dmso-d6
(δ(1H), 2.50 ppm; δ(13C), 39.52 ppm),26d CDCl3 (δ(1H), 7.26 ppm;
δ(13C), 77.16 ppm),26d D3CCN (δ(1H), 1.94 ppm; δ (13C), 1.32
ppm),26d CD2Cl2 (δ(1H), 5.32 ppm; δ (13C), 54.00 ppm),26e and
Cl2DCCDCl2 (δ(1H), 5.91 ppm).26f For the assignment of the proton
signals various 2D-NMR methods were carried out (1H−1H-COSY,
HSQC, HMBC, TOCSY, NOESY, 15N-HSQC). Elemental analyses
were carried out by the central elemental analysis section of the
Department of Chemistry at the University of Hamburg. Air-sensitive
compounds were analyzed on an Elementar Vario EL III instrument,
and nonsensitive compounds were analyzed on a Carlo Erba EA 1108
CHNS-O instrument. EI-MS and ESI-HRMS measurements were
carried out by the MS section of the Institute of Organic Chemistry of
the University of Hamburg with a Finnigan MAT 311 A instrument at
97,26p and CrySalisPro 26q The diffuse contribution to the total electron
.
density generated by partially cocrystallized solvent molecules in the
data sets of 34, 35, and 39 was treated by the subprogram sqeeze from
the program Platon.26r The crystallographic data tables are deposited
in the Supporting Information (S1).
In Vitro Cytotoxicity Studies..25a−c The microtiter plate method
used for testing of antiproliferative properties is based on crystal violet
staining of cells and has been described in detail elsewhere.25a,b All of
the cells were obtained from the German Collection of Micro-
organisms and Cell Cultures (DSMZ) (Braunschweig, FRG) and
cultured at 37 °C under a humidified atmosphere of 5% CO2/air in
RPMI-1640 culture medium supplemented with 10% fetal calf serum
and the antibiotics streptomycin and benzylpenicillin. Stock solutions
of compounds were prepared in DMSO and diluted 1000-fold with
cell culture medium (RPMI medium + 10% fetal calf serum) for
testing. The cells were seeded out (500−1000 cells/well in 100 mL)
24 h before testing, and drug treatment took place for 96 h. Cell
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growth was stopped after 96 h by the addition of a 1% glutaraldehyde
solution. The cells were later stained with a 0.02% crystal violet
solution in water. Excess dye was washed out with water, and cell-
bound dye was taken back into solution with a 70% ethanol/water
mixture.
The optical density of the crystal violet was determined at λ 570 nm
with an Anthos 2010 microtiter plate reader. For IC50 determinations,
all substances were tested at three serially diluted concentrations. The
corrected T/C values ((T/C)corr) for each concentration were
calculated with the equation
2J6a,6b = 10.2 Hz, 1 H, Ha-6), 3.76−3.64 (m, 3 H, H-4, Hb-6, Hb-N-3),
3
3
3.52 (ddd, J5,6a = 4.8 Hz, J = 14.5 Hz, 1 H, H-5), 3.41 (s, 3 H,
OCH3), 3.02−2.89 (m, 2 H, H-2, Hb-N-2), 2.73 (m, 1 H, H-3) ppm.
13C NMR (75 MHz, CD2Cl2): δ 129.2 (C4′), 128.2 (C3′), 126.3
(C2′), 101.7 (C7), 98.3 (C1), 83.4 (C6H6), 80.3 (C4), 68.5 (C6), 63.2
(C5), 59.9 (C2), 55.4 (OCH3), 53.6 (C3) ppm.
[T-4-S]-Chlorido-η6-p-cymene(methyl 2,3-diamino-4,6-O-benzyli-
dene-2,3-dideoxy-α-D-glucopyranoside)ruthenium(II) Tetrafluorido-
borate (37; 85% Yield). Yellow powder. [α (dichloromethane, 25 °C,
589 nm) = −48°. Anal. Found: C, 45.55; H, 5.42; N, 4.65. Calcd for
C24H34BClF4N2O4Ru: C, 45.19; H, 5.37; N, 4.39. 1H NMR (400
MHz, CD2Cl2): δ 7.50−7.44 (m, 2 H, H-2′), 7.40−7.35 (m, 3 H, H-3′,
H-4′), 5.73, 5.67, 5.55, 5.51 (m, 4 H, H-2″, H-3″, H-5″, H-6″), 5.59 (s,
1 H, H-7), 5.31 (m, 1 H, Ha-N-2), 5.04 (d, 1 H, H-1), 4.83 (m, 1 H,
Ha-N-3), 4.22 (dd, 3J6a,5 = 4.8 Hz, 2J6a,6b = 10.2 Hz, 1 H, Ha-6), 3.80−
3.69 (m, 2 H, H-4, Hb-6), 3.59−3.51 (m, 2 H, H-5, Hb-N-3), 3.43 (s,
3 H, OCH3), 3.02 (m, 1 H, Hb-N-2), 2.97−2.85 (m, 2 H, H-2,
CH(CH3)2), 2.79 (m, 1 H, H-3), 2.30 (s, 3 H, CH3), 1.31, 1.29 (m, 6
H, CH(CH3)2) ppm. 1H NMR (400 MHz, dmso-d6): δ 7.54−7.45 (m,
2 H, H-2′), 7.41−7.34 (m, 3 H, H-3′, H-4′), 6.58 (m, 1 H, Ha-N-2),
5.81 (m, 1 H, Ha-N-3), 5.65 (s, 1 H, H-7), 5.59, 5.49 (m, 4 H, H-2″,
H-3″, H-5″, H-6″), 5.38 (m, 1 H, Hb-N-3), 4.85 (d, 1 H, H-1), 4.22
(dd, 1 H, Ha-6), 3.76 (m, 1 H, Hb-6), 3.61 (dd, 1 H, H-4), 3.41−3.29
(m, 4 H, OCH3, H-5 [3.36 {s, 3 H, OCH3}]), 2.86 (m, 1 H,
CH(CH3)2), 2.77 (m, 1 H, Hb-N-2), 2.50−2.31 (m, 2 H, H-2, H-3),
2.18 (s, 3 H, CH3), 1.22, 1.20 (m, 6 H, CH(CH3)2) ppm. 13C NMR
(75 MHz, CD2Cl2): δ 129.7 (C4′), 128.7 (C3′), 126.9 (C2′), 102.4
(C7), 98.8 (C1), 83.8, 83.3, 80.9, 80.7 (C2″, C3″, C5″, C6″), 80.8
(C4), 69.0 (C6), 63.7 (C5), 60.2 (C2), 55.9 (OCH3), 54.1 (C3), 31.3
(CH(CH3)2), 23.2, 22.5 (CH(CH3)2), 18.4 (CH3) ppm. 13C NMR
(100 MHz, dmso-d6): δ 137.3 (C1′), 129.0 (C4′), 128.1 (C3′), 126.4
(C2′), 104.5 (C4″), 100.8 (C7), 98.0 (C1), 95.8 (C1″), 81.1, 80.8,
80.1 (C2″, C3″, C5″, C6″), 80.8 (C4), 67.6 (C6), 63.0 (C5), 59.6
(C2), 55.2 (OCH3), 52.9 (C3), 30.0 (CH(CH3)2), 22.7, 21.6
(CH(CH3)2), 17.4 (CH3) ppm. 15N NMR (shifts from 15N HSQC,
dmso-d6; NH3, δN 0 ppm, calcd): δ 4.4 (N-2), −0.1 (N-3) ppm.
[T-4-S]-Chlorido(methyl 2,3-diamino-4,6-O-benzylidene-2,3-di-
deoxy-α-D-glucopyranoside)-η6-(1″,2″,3″,4″-tetrahydro-
naphthalene)ruthenium(II) Tetrafluoridoborate (38; 82% Yield).
Yellow powder. [α](dichloromethane, 25 °C, 589 nm) = −74°. Anal.
Found: C, 44.70; H, 5.15; N, 3.99. Calcd for C48H66B2Cl2F8N4O9Ru
(NMR: 2[C24H32ClN2O4Ru]BF4·H2O): C, 44.70; H, 5.16 N, 4.34; the
compound contains 1/2 equiv of water. HRMS (esi): m/z 549.1126
(T/C)corr (%) = (ODT − ODC,0)/(ODC − ODC,0A) × 100
where T is the optical density at λ 570 nm (OD570) of the treated cells
after 96 h of treatment time, ODC is the OD570 value of the untreated
cells after 96 h of growth without substance, and ODC,0 is the OD570
value of the cells at the time of treatment (i.e., 96 h before T and C).
Linear regression analysis of the log concentration versus (T/C)corr
plots was used to estimate the concentration of substance that caused
(T/C)corr = 50% (IC50). The T/C values from the primary screening
are deposited in the Supporting Information (S4).
General Procedure for the Synthesis of Monocationic
Complexes by Means of Silver Tetrafluoridoborate. The
complex precursor 33a (141 mg, 0.18 mmol), 10 (99 mg, 0.35
mmol), and silver tetrafluoridoborate (69 mg, 0.35 mmol) were stirred
in dichloromethane (15 mL) in the absence of light for 4 h. Then, the
solution was filtered, reduced to a few milliliters (just before
precipitation of the product), covered with a layer of diethyl ether,
and cooled in a refrigerator (−20 °C). The yellow precipitate of 34
(229 mg, 0.31 mmol; 89% yield) was washed with diethyl ether and
then dried under vacuum.
[T-4-S]-Chlorido(methyl 2,3-diamino-4,6-O-benzylidene-2,3-di-
deoxy-α-D-glucopyranoside)pentamethyl-η5-cyclopentadienyl-
iridium(III) Tetrafluoridoborate (34). Yellow powder. [α]-
(dichloromethane, 25 °C, 589 nm) = −51°. Anal. Found: C, 40.64;
H, 5.35; N, 3.88. Calcd for C52H80B2Cl2F8Ir2N4O9 (X-ray: 2-
[C24H35ClIrN2O4]BF4·C4H10O): C, 40.71; H, 5.26; N, 3.65; the
1
compound contains 1/2 equiv of diethyl ether. H NMR (400 MHz,
CD2Cl2): δ 7.52−7.47 (m, 2 H, H-2′), 7.40−7.35 (m, 3 H, H-3′, H-
4′), 5.63 (s, 1 H, H-7), 5.12 (d, 3J1,2 = 3.3 Hz, 1 H, H-1), 5.05 (m, 1 H,
Ha-N-2), 4.66 (m, 1 H, Ha-N-3), 4.26 (dd, 1 H, Ha-6), 3.95−3.84 (m,
2 H, H-4, Hb-N-3), 3.81−3.69 (m, 2 H, Hb-6, Hb-N-2), 3.64 (ddd, 1
H, H-5), 3.48 (s, 3 H, OCH3), 3.34 (m, 1 H, H-3), 2.93 (m, 1 H, H-2),
1.76 (s, 15 H, C5(CH3)5) ppm. 13C NMR (shifts from HSQC,
CD2Cl2): δ 129.3 (C4′), 128.5 (C3′), 126.9 (C2′), 102.3 (C7), 99.1
(C1), 80.1 (C4), 69.0 (C6), 64.2 (C5), 60.6 (C2), 56.0 (C3), 55.8
(OCH3), 9.3 (C5(CH3)5) ppm.
1
(100%, [M]+, calcd 549.1094). H NMR (300 MHz, CD2Cl2): 7.50−
7.44 (m, 2 H, H-2′), 7.39−7.33 (m, 3 H, H-3′, H-4′), 5.78−5.42 (m, 6
H, H-7, H-5″, H-6″, H-7″, H-8″, Ha-N-2), 5.19 (m, 1 H, Ha-N-3),
4.99 (d, 1 H, H-1), 4.14 (dd, 3J6a,5 = 4.8 Hz, 2J6a,6b = 10.3 Hz, 1 H, Ha-
6), 3.75−3.65 (m, 2 H, H-4, Hb-6), 3.57−3.48 (m, 1 H, H-5), 3.42 (s,
3 H, OCH3), 3.37 (m, 1 H, Hb-N-3), 2.98−2.42 (m, 7 H, H-2, H-3,
H-1″, H-4″, Hb-N-2), 2.01−1.65 (m, 4 H, H-2″, H-3″) ppm. 13C
NMR (75 MHz, CD2Cl2): δ 129.1 (C4′), 128.2 (C3′), 126.4 (C2′),
101.9 (C7), 98.5 (C1), 82.7, 82.4, 80.4, 80.3 (C5″, C6″, C7″, C8″),
79.4 (C4), 68.5 (C6), 63.2 (C5), 55.4 (OCH3), 60.2, 53.4 (C2, C3),
26.8, 26.4 (C1″, C4″), 21.5, 21.4 (C2″, C3″) ppm.
[T-4-S]-Chlorido(methyl 2,3-diamino-4,6-O-benzylidene-2,3-di-
deoxy-α-D-glucopyranoside)pentamethyl-η5-cyclopentadienyl-
rhodium(III) Tetrafluoridoborate (35; 84% Yield). Orange-yellow
powder. [α](dichloromethane, 25 °C, 589 nm) = −37°. Anal. Found:
C, 45.64; H, 6.16; N, 4.28. Calcd for C52H80B2Cl2F8Rh2N4O9 (X-ray:
2[C24H35ClN2O4Rh]BF4·C4H10O): C, 46.07; H, 5.95; N, 4.13; the
1
compound contains 1/2 equiv of diethyl ether. H NMR (400 MHz,
CD2Cl2): δ 7.51−7.46 (m, 2 H, H-2′), 7.39−7.35 (m, 3 H, H-3′, H-
4′), 5.61 (s, 1 H, H-7), 5.04 (d, 3J1,2 = 3.0 Hz, 1 H, H-1), 4.38 (m, 1 H,
Ha-N-2), 4.25−4.13 (m, 2 H, Ha-6, Ha-N-3), 3.88 (dd, 1 H, H-4),
3.74 (dd, 1 H, Hb-6), 3.61−3.47 (m, 2 H, H-5, Hb-N-3), 3.45 (s, 3 H,
OCH3), 3.28 (m, 1 H, Hb-N-2), 3.10 (m, 1 H, H-3), 2.97 (m, 1 H, H-
2), 1.78 (s, 15 H, C5(CH3)5) ppm. 13C NMR (shifts from HSQC,
CD2Cl2): δ 129.3 (C4′), 128.5 (C3′), 126.8 (C2′), 102.4 (C7), 99.1
(C1), 81.0 (C4), 68.9 (C6), 63.8 (C5), 58.8 (C2), 55.9 (OCH3), 54.8
(C3), 9.1 (C5(CH3)5) ppm.
[T-4-R]- and [T-4-S]-Chlorido(methyl 2,3-diamino-4,6-O-benzyli-
dene-2,3-dideoxy-α-D-mannopyranoside)pentamethyl-η5-cyclo-
pentadienylrhodium(III) Tetrafluoridoborate (39; Ratio ca. 1:1; 87%
Yield). Orange-yellow powder. Anal. Found: C, 44.71; H, 5.60; N,
4.09. Calcd for C24H35BClF4N2O4Rh: C, 44.99; H, 5.51; N, 4.37.
1
Data for [T-4-R] are as follows. H NMR (400 MHz, CD2Cl2): δ
7.55−7.29 (m, 5 H, H-2′, H-3′, H-4′), 5.50 (s, 1 H, H-7), 4.95 (d, 1 H,
H-1), 4.69 (m, 1 H, Ha-N-2), 4.26 (dd, 1 H, H-4), 4.15 (dd, 1 H, Ha-
6), 4.09 (m, 1 H, Ha-N-3), 3.87 (m, 1 H, H-5), 3.81 (m, 1 H, Hb-N-
3), 3.69 (m, 1 H, Hb-6), 3.63 (m, 1 H, H-3), 3.39 (s, 3 H, OCH3),
3.27 (m, 1 H, H-2), 3.22 (m, 1 H, Hb-N-2), 1.75 (m, 15 H, C5(CH3)5)
ppm. 13C NMR (100 MHz, shifts partially from HSQC, CD2Cl2): δ
130.1 (C4′), 129.0 (C3′), 126.9 (C2′), 102.7 (C7), 100.5 (C1), 74.2
(C4), 69.2 (C6), 63.0 (C5), 61.6 (C2), 56.0 (OCH3), 53.7 (C3), 9.2
(C5(CH3)5) ppm. 15N NMR (shifts from 15N HSQC, CD2Cl2; NH3,
δN 0 ppm, calcd): δ 14.2 (N-2), 10.7 (N-3) ppm.
[T-4-S]-η6-Benzenechlorido(methyl 2,3-diamino-4,6-O-benzyli-
dene-2,3-dideoxy-α-D-glucopyranoside)ruthenium(II) Tetrafluorido-
borate (36; 88% Yield). Yellow powder. [α](dichloromethane, 25 °C,
589 nm) = −43°. Anal. Found: C, 41.65; H, 4.83; N, 4.94. Calcd for
C20H26BClF4N2O4Ru: C, 41.29; H, 4.50; N, 4.82. 1H NMR (400
MHz, CD2Cl2): δ 7.48−7.43 (m, 2 H, H-2′), 7.40−7.34 (m, 3 H, H-3′,
H-4′), 5.90 (m, 1 H, Ha-N-2), 5.79 (s, 6 H, C6H6), 5.56 (s, 1 H, H-7),
3
5.31 (m, 1 H, Ha-N-3), 5.00 (d, 1 H, H-1), 4.20 (dd, J6a,5 = 4.8 Hz,
1517
DOI: 10.1021/om5013117
Organometallics 2015, 34, 1507−1521

Organometallics
Article
1
Data for [T-4-S] are as follows. H NMR (400 MHz, CD2Cl2): δ
7.55−7.29 (m, 5 H, H-2′, H-3′, H-4′), 5.63 (s, 1 H, H-7), 4.86 (d, 1 H,
H-1), 4.50 (m, 1 H, Ha-N-3), 4.33 (dd, 1 H, Ha-6), 3.97 (dd, 1 H, Hb-
6), 3.71 (m, 1 H, Ha-N-2), 3.70 (m, 1 H, H-5), 3.55 (m, 1 H, Hb-N-
2), 3.53 (m, 1 H, H-2), 3.43 (m, 1 H, Hb-N-3), 3.40 (dd, 1 H, H-4),
3.38 (s, 3 H, OCH3), 3.28 (m, 1 H, H-3), 1.80 (m, 15 H, C5(CH3)5)
ppm. 13C NMR (100 MHz, shifts partially from HSQC, CD2Cl2): δ
129.8 (C4′), 128.8 (C3′), 126.7 (C2′), 102.9 (C7), 99.9 (C1), 75.5
(C4), 69.1 (C6), 63.3 (C5), 56.8 (C3), 56.2 (OCH3), 55.2 (C2), 9.7
(C5(CH3)5) ppm. 15N NMR (shifts from 15N HSQC, CD2Cl2; NH3,
δN 0 ppm, calcd): δ 12.7 (N-2), 5.3 (N-3) ppm.
C8″), 74.1 (C4), 68.0 (C6), 62.7 (C5), 56.0 (C3), 55.4 (OCH3), 54.6
(C2), 27.0, 26.3 (C1″, C4″), 21.5 (C2″, C3″) ppm. 15N NMR (shifts
from 15N HSQC, CD2Cl2; NH3, δN 0 ppm, calcd): δ 2.7 (N-2), −1.2
(N-3) ppm.
[T-4-R]-Chlorido(methyl 2,3-diamino-4,6-O-benzylidene-2,3-di-
deoxy-α-D-gulopyranoside)pentamethyl-η5-cyclopentadienyl-
rhodium(III) Tetrafluoridoborate (42; 58% Yield). The crude product
was extracted from the reaction residue with hot 1,2-dichloroethane
due to its low solubility. Orange-yellow powder. [α](dichloromethane,
25 °C, 589 nm) = 135°. Anal. Found: C, 42.26; H, 5.03; N, 3.58. Calcd
for C26H39BCl3F4N2O4Rh (X-ray: [C24H35ClN2O4Rh]BF4·C2H4Cl2):
C, 42.22; H, 5.31; N, 3.79; the compound contains 1 equiv of 1,2-
[T-4-R]- and [T-4-S]-Chlorido-η6-p-cymene(methyl 2,3-diamino-
4,6-O-benzylidene-2,3-dideoxy-α-D-mannopyranoside)ruthenium-
(II)Tetrafluoridoborate (40; Ratio ca. 1:3; 82% Yield). Yellow powder.
Anal. Found: C, 44.99; H, 5.38; N, 4.17. Calcd for
C24H34BClF4N2O4Ru: C, 45.19; H, 5.37; N, 4.39.
1
dichloroethane. H NMR (300 MHz, CD2Cl2): δ 7.45−7.31 (m, 5 H,
H-2′, H-3′, H-4′), 5.56 (s, 1 H, H-7), 4.95 (d, 1 H, H-1), 4.30−4.17
(m, 3 H, H-4, H-6), 4.02 (m, 1 H, H-5), 3.60−3.38 (m, 5 H, H-2, H-3,
OCH3 {3.55 [s, 3 H, OCH3], 3.43 [m, 1 H, H-2]}), 1.75 (s, 15 H,
C5(CH3)5) ppm. 1H NMR (300 MHz, acetone-d6): δ 7.45−7.30 (m, 5
H, H-2′, H-3′, H-4′), 5.63 (s, 1 H, H-7), 5.02 (d, 1 H, H-1), 4.90−4.52
(m, 3 H, H−N), 4.30 (dd, 1 H, H-4), 4.20 (m, 2 H, H-6), 4.10 (m, 1
H, H-5), 3.65−3.48 (m, 5 H, H-3, OCH3, H−N {3.61 [s, 3 H,
OCH3]}), 3.43 (m, 1 H, H-2), 1.81 (s, 15 H, C5(CH3)5) ppm. 13C
NMR (shifts from HSQC, acetone-d6): δ 128.8 (C3′), 127.0 (C2′),
101.6 (C7), 99.2 (C1), 75.7 (C4), 71.0 (C3), 69.6 (C6), 55.6
(OCH3), 50.6 (C2), 9.2 (C5(CH3)5) ppm. UV/vis (dichloromethane
λmax (ε [M−1 cm−1]): 369 (1423) nm.
1
Data for [T-4-R] are as follows. H NMR (400 MHz, CD2Cl2): δ
7.52−7.32 (m, 5 H, H-2′, H-3′, H-4′), 6.04−5.41 (m, 6 H, H-2″, H-3″,
H-5″, H-6″, Ha-N-2, Ha-N-3), 5.42 (s, 1 H, H-7), 4.94 (d, 1 H, H-1),
4.17 (dd, 1 H, Ha-6), 3.99 (m, 1 H, H-4), 3.73 (m, 1 H, H-5), 3.63 (m,
1 H, Hb-6), 3.60−3.48 (m, 1 H, H-3), 3.40−3.27 (m, 2 H, H-2, Hb-N-
3), 3.33 (s, 3 H, OCH3), 3.06−2.86 (m, 2 H, Hb-N-2, CH(CH3)2),
2.26 (s, 3 H, CH3), 1.36−1.24 (m, 6 H, CH(CH3)2) ppm. 13C NMR
(100 MHz, CD2Cl2): δ 129.8 (C4′), 128.7 (C3′), 126.8 (C2′), 102.5
(C7), 100.3 (C1), 84.8, 83.8, 83.0, 80.1 (C2″, C3″, C5″, C6″), 74.2
(C4), 69.1 (C6), 63.3 (C5), 62.7 (C2), 55.9 (OCH3), 53.1 (C3), 31.1
(CH(CH3)2), 23.2, 22.4 (CH(CH3)2), 18.2 (CH3) ppm. 15N NMR
(shifts from 15N HSQC, CD2Cl2; NH3, δN 0 ppm, calcd): δ 5.7 (N-2),
−4.8 (N-3) ppm.
[T-4-R]-Chlorido-η6-p-cymene(methyl 2,3-diamino-4,6-O-benzyli-
dene-2,3-dideoxy-α-D-gulopyranoside)ruthenium(II) Tetrafluorido-
borate (44; 81% Yield). Yellow powder. [α](dichloromethane, 25
°C, 589 nm) = 106°. [α](acetone, 25 °C, 589 nm) = 114°. Anal.
Found: C, 45.25; H, 5.48; N, 4.33. Calcd for C24H34BClF4N2O4Ru: C,
1
Data for [T-4-S] are as follows. H NMR (400 MHz, CD2Cl2): δ
1
45.19; H, 5.37; N, 4.39. H NMR (300 MHz, CD2Cl2): δ 7.45−7.36
7.52−7.32 (m, 5 H, H-2′, H-3′, H-4′), 6.04−5.41 (m, 5 H, H-2″, H-3″,
H-5″, H-6″, Ha-N-3), 5.71 (s, 1 H, H-7), 4.82 (d, 1 H, H-1), 4.71 (m,
1 H, Ha-N-2), 4.26 (dd, 1 H, H-6a), 4.10 (dd, 1 H, H-6b), 3.83 (m, 1
H, H-5), 3.64 (dd, 1 H, H-4), 3.60−3.48 (m, 2 H, H−N-2b, H−N-3b),
3.40−3.27 (m, 1 H, H-2), 3.36 (s, 3 H, OCH3), 3.06−2.86 (m, 2 H, H-
3, CH(CH3)2), 2.21 (s, 3 H, CH3), 1.36−1.24 (m, 6 H, CH(CH3)2)
ppm. 13C NMR (100 MHz, CD2Cl2): δ 137.4 (C1′), 130.0 (C4′),
129.0 (C3′), 126.7 (C2′), 104.8 (C4″), 102.5 (C7), 99.3 (C1), 97.7
(C1″), 87.6, 81.8, 80.5, 80.2 (C2″, C3″, C5″, C6″), 74.4 (C4), 68.5
(C6), 63.2 (C5), 56.4 (C3), 56.0 (OCH3), 55.0 (C2), 31.6
(CH(CH3)2), 23.9, 21.7 (CH(CH3)2), 18.9 (CH3) ppm. 15N NMR
(shifts from 15N HSQC, CD2Cl2; NH3, δN 0 ppm, calcd): δ 4.2 (N-2),
−1.3 (N-3) ppm.
(m, 2 H, H-2′), 7.33−7.23 (m, 3 H, H-3′, H-4′), 5.72−5.19 (m, 6 H,
H-7, H-2″, H-3″, H-5″, H-6″, Ha-N-2), 4.98 (d, 1 H, H-1), 4.93 (m, 1
H, H-aN-3), 4.32−3.89 (m, 5 H, H-4, H-5, H-6, Hb-N-3), 3.52 (s, 3
H, OCH3), 3.49 (m, 1 H, Hb-N-2), 3.20 (m, 1 H, H-2), 3.09 (m, 1 H,
H-3), 2.78 (m, 1 H, CH(CH3)2), 2.15 (s, 3 H, CH3), 1.20 (dd, 6 H,
CH(CH3)2) ppm. 13C NMR (75 MHz, CD2Cl2): δ 129.3 (C4′), 128.4
(C3′), 126.3 (C2′), 101.2 (C7), 98.1 (C1), 85.5, 83.0, 80.1. 79.9 (C2″,
C3″, C5″, C6″), 73.9 (C4), 69.2 (C6), 58.2 (C5), 55.4 (OCH3), 54.6
(C3), 49.8 (C2), 30.8 (CH(CH3)2), 22.8, 22.1 (CH(CH3)2), 17.9
(CH3) ppm.
[T-4-S]-Chlorido(methyl 2,3-diamino-4,6-O-benzylidene-2,3-di-
deoxy-α-D-talopyranoside)pentamethyl-η5-cyclopentadienyl-
rhodium(III) Tetrafluoridoborate (46; 80% Yield). Orange-yellow
powder. [α](dichloromethane, 25 °C, 589 nm) = 56°. Anal. Found: C,
44.76; H, 5.65; N, 4.68. Calcd for C24H35BClF4N2O4Rh: C, 44.99; H,
5.51; N, 4.37. 1H NMR (300 MHz, CD2Cl2): δ 7.68−7.60 (m, 2 H, H-
2′), 7.48−7.40 (m, 3 H, H-3′, H-4′), 5.68 (s, 1 H, H-7), 4.89 (d, 1 H,
H-1), 4.57−4.48 (m, 2 H, H-4, Ha-N-3), 4.23 (dd, 1 H, Ha-6), 4.13
(dd, 1 H, Hb-6), 3.80 (m, 1 H, Ha-N-2), 3.63 (m, 1 H, H-5), 3.62−
3.50 (m, 2 H, H-2, Hb-N-3), 3.44−3.36 (m, 1 H, H-3), 3.35 (s, 3 H,
OCH3), 3.24 (m, 1 H, Hb-N-2), 1.37 (s, 15 H, C5(CH3)5) ppm. 13C
NMR (75 MHz, CD2Cl2): δ 130.0 (C4′), 128.7 (C3′), 127.8 (C2′),
103.3 (C7), 100.6 (C1), 73.4 (C4), 69.4 (C6), 62.4 (C5), 55.2
(OCH3), 53.8 (C2), 49.2 (C3), 8.5 (C5(CH3)5) ppm. UV/vis
(dichloromethane λmax (ε [M−1 cm−1]): 376 (2587) nm.
[T-4-R]- and [T-4-S]-Chlorido(methyl 2,3-diamino-4,6-O-benzyli-
dene-2,3-dideoxy-α-D-mannopyranoside)-η6-(1″,2″,3″,4″-tetra-
hydronaphthalene)ruthenium(II) Tetrafluoridoborate (41; Ratio ca.
1:2; 82% Yield). Yellow powder. Anal. Found: C, 44.85; H, 5.21; N,
4.34. Calcd for C48H66B2Cl2F8N4O9Ru (NMR: 2[C24H32ClN2O4Ru]-
BF4·H2O): C, 44.70; H, 5.16 N, 4.34; the compound contains 1/2
equiv of water.
1
Data for [T-4-R] are as follows. H NMR (400 MHz, CD2Cl2): δ
7.60−7.30 (m, 5 H, H-2′, H-3′, H-4′), 6.18 (m, 1 H, Ha-N-3), 6.01
(m, 1 H, Ha-N-2), 5.93−5.26 (m, 4 H, H-5″, H-6″, H-7″, H-8″), 5.44
(s, 1 H, H-7), 4.92 (d, 1 H, H-1), 4.29−4.08 (m, 1 H, Ha-6), 4.02 (m,
1 H, H-4), 3.87−3.60 (m, 2 H, H-5, Hb-6), 3.58−3.23 (m, 2 H, H-2,
H-3), 3.29 (s, 3 H, OCH3), 3.16−2.46 (m, 6 H, H-1″, H-4″, Hb-N-2,
Hb-N-3), 1.98−1.62 (m, 4 H, H-2″, H-3″) ppm. 13C NMR (75 MHz,
CD2Cl2): δ 129.2 (C4′), 128.2 (C3′), 126.3 (C2′), 102.0 (C7), 98.8
(C1), 83.5, 82.3, 80.3 (C5″, C6″, C7″, C8″), 73.8 (C4), 68.6 (C6),
62.8 (C5), 62.4, (C2), 55.2 (OCH3), 52.4 (C3), 27.0, 26.2 (C1″,
C4″), 21.5 (C2″, C3″) ppm. 15N NMR (shifts from 15N HSQC,
CD2Cl2; NH3, δN 0 ppm, calcd): δ 4.0 (N-2), −6.0 (N-3) ppm.
[T-4-S]-Chlorido-η6-p-cymene(methyl 2,3-diamino-4,6-O-benzyli-
dene-2,3-dideoxy-α-D-talopyranoside)ruthenium(II) Tetrafluorido-
borate (47; 85% Yield). Yellow powder. [α](dichloromethane, 25
°C, 589 nm) = 56°. Anal. Found: C, 45.42; H, 5.50; N, 4.24. Calcd for
C24H34BClF4N2O4Ru: C, 45.19; H, 5.37; N, 4.39. 1H NMR (300
MHz, CD2Cl2): δ 7.84−7.77 (m, 2 H, H-2′), 7.56−7.41 (m, 3 H, H-3′,
H-4′), 5.72 (s, 1 H, H-7), 5.66 (m, 1 H, Ha-N-2), 5.49, 5.05, 4.69, 4.30
(m, 4 H, H-2″, H-3″, H-5″, H-6″), 4.92 (d, 1 H, H-1), 4.59 (m, 1 H,
Ha-N-3), 4.51 (dd, 1 H, H-4), 4.26 (dd, 1 H, Ha-6), 4.14 (dd, 1 H,
Hb-6), 3.71 (m, 1 H, Hb-N-3), 3.60 (m, 1 H, H-5), 3.40 (m, 1 H, Hb-
N-2), 3.35 (s, 3 H, H-7), 3.21 (m, 1 H, H-2), 2.97 (m, 1 H, H-3), 2.69
(m, 1 H, CH(CH3)2), 1.91 (s, 3 H, CH3), 1.19 (m, 6 H, CH(CH3)2)
ppm. 13C NMR (75 MHz, CD2Cl2): δ 130.4 (C4′), 129.2 (C3′), 127.4
(C2′), 102.2 (C7), 100.0 (C1), 85.0, 82.8, 81.4, 80.3 (C2″, C3″, C5″,
1
Data for [T-4-S] are as follows. H NMR (400 MHz, CD2Cl2): δ
7.60−7.30 (m, 5 H, H-2′, H-3′, H-4′), 5.93−5.26 (m, 5 H, H-5″, H-6″,
H-7″, H-8″, Ha-N-3), 5.78 (s, 1 H, H-7), 4.84 (d, 1 H, H-1), 4.77 (m,
1 H, Ha-N-2), 4.29−4.08 (m, 2 H, H-6), 3.87−3.60 (m, 3 H, H-4, H-5,
Hb-N-3), 3.58−3.23 (m, 2 H, H-2, Hb-N-2), 3.36 (s, 3 H, OCH3),
3.16−2.46 (m, 5 H, H-3, H-1″, H-4″), 1.98−1.62 (m, 4 H, H-2″, H-
3″) ppm. 13C NMR (75 MHz, CD2Cl2): δ 129.4 (C4′), 128.4 (C3′),
126.4 (C2′), 102.0 (C7), 100.0 (C1), 84.4, 81.0, 79.8 (C5″, C6″, C7″,
1518
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Article
C6″), 72.9 (C4), 69.6 (C6), 62.6 (C5), 55.7 (OCH3), 53.7 (C3), 50.2
(C2), 31.1 (CH(CH3)2), 22.9, 22.7 (CH(CH3)2), 18.0 (CH3) ppm.
[T-4-S]-Chlorido(methyl 2,3-diamino-4,6-O-benzylidene-2,3-di-
deoxy-α-D-talopyranoside)-η6-(1″,2″,3″,4″-tetrahydronaphthalene)-
ruthenium(II) Tetrafluoridoborate (48; 79% Yield). Yellow powder.
[α](dichloromethane, 25 °C, 589 nm) = −52°. Anal. Found: C, 44.82;
H, 5.20; N, 4.36. Calcd for C48H66B2Cl2F8N4O9Ru (NMR: 2-
[C24H32ClN2O4Ru]BF4·H2O): C, 44.70; H, 5.16 N, 4.34; the
compound contains 1/2 equiv of water. HRMS (ESI): m/z
549.1105 (100%, [M]+, calcd 549.1094). 1H NMR (300 MHz,
CD2Cl2): δ 7.81−7.74 (m, 2 H, H-2′), 7.55−7.41 (m, 3 H, H-3′, H-
4′), 5.91 (m, 1 H, Ha-N-2), 5.72 (s, 1 H, H-7), 5.16, 5.08, 5.00, 3.94
(m, 4 H, H-5″, H-6″, H-7″, H-8″), 4.86 (d, 1 H, H-1), 4.80 (m, 1 H,
Ha-N-3), 4.51 (dd, 1 H, H-4), 4.26 (dd, 1 H, Ha-6), 4.13 (dd, 1 H,
Hb-6), 3.59 (m, 1 H, H-5), 3.36 (s, 3 H, OCH3), 3.32−2.98 (m, 4 H,
H-2, H-3, Hb-N-2, Hb-N-3), 2.92−2.24, 1.97−1.61 (m, 8 H, H-1″, H-
δ 7.36 (m, 5 H, H-2′, H-3′, H-4′), 6.35 (m, 1 H, Ha-N-2), 5.75−5.24
(m, 6 H, H-7, H-5″, H-6″, H-7″, H-8″, Ha-N-3), 5.15 (m, 1 H, Hb-N-
3), 4.72 (d, 1 H, H-1), 4.28−4.04 (m, 4 H, H-4, H-6, Hb-N-2), 3.92
(m, 1 H, H-5), 3.34 (s, 3 H, OCH3), 3.30−2.68 (m, 4 H, H-2, H-3, H-
1″, H-4″), 2.59−2.37 (m, 2 H, H-1″, H-4″), 1.90−1.55 (m, 4 H, H-2″,
H-3″) ppm. 13C NMR (75 MHz, dmso-d6): δ 129.3 (C4′), 128.5
(C3′), 126.4 (C2′), 100.2 (C7), 97.8 (C1), 83.5, 82.0, 80.7, 80.5 (C5″,
C6″, C7″, C8″), 73.7 (C4), 68.8 (C6), 58.4 (C5), 55.2 (OCH3), 54.6
(C2), 50.1 (C3), 26.2, 26.1 (C1″, C4″), 21.6, 21.5 (C2″, C3″) ppm.
General Procedure for the Synthesis of Uncharged η1-
Amino Complexes. The complex precursor 33e (35.8 mg, 0.059
mmol) and the ligand 12 (51.2 mg, 0.12 mmol) were stirred in
dichloromethane (10 mL) for 2 h. The solution was filtered, reduced
to a few milliliters (just before precipitation of the product), covered
with a layer of n-hexane, and cooled in a refrigerator (−20 °C). The
orange precipitate of 51 (79 mg, 0.11 mmol; 91%) was washed with
diethyl ether and then dried under vacuum.
1
2″, H-3″, H-4″) ppm. H NMR (300 MHz, acetone-d6): δ 7.90−7.80
Dichlorido-η1-(methyl 2-amino-4,6-O-benzylidene-2,3-dideoxy-3-
tosylamido-α-D-glucopyranoside)-η6-(1″,2″,3″,4″-tetrahydro-
naphthalene)ruthenium(II) (51). Orange powder. [α]-
(dichloromethane, 25 °C, 589 nm) = −13°. Anal. Found: C, 49.87;
H, 5.23; N, 3.71; S; 3.83. Calcd for C62H78Cl4N4O13Ru2S2
{2[C31H38Cl2N2O6RuS]·H2O}: C, 49.80; H, 5.26; N, 3.75; S, 4.29;
the compound contains 1/2 equiv of water. HRMS (ESI): m/z
703.1167 (2%, [M − Cl]+, calcd 703.1183), 667.1409 (18%, [M − Cl
− HCl]+, calcd 667.1416). 1H NMR (300 MHz, CD2Cl2): δ 7.68, 6.91
(AA′BB′, 4 H, H-2′, H-3′), 7.42−7.23, 7.12 (m, 6 H, H-2″, H-3″, H-
4″), 6.54 (s, 1 H, H−N-3), 5.74−5.25 (m, 6 H, H-7, H-5‴, H-6‴, H-
7‴, H-8‴, Ha-N-2), 5.02 (d, 1 H, H-1), 4.08 (dd, 1 H, H-6a), 3.70−
3.43 (m, 4 H, H-3, H-5, Hb-6, Hb-N-2), 3.36 (s, 3 H, OCH3), 3.36−
2.96, 2.48 (m, 6 H, H-2, H-4, H-1‴, H-4‴), 2.23 (s, 3 H, (CO)CH3),
(m, 2 H, H-2′), 7.56−7.43 (m, 3 H, H-3′, H-4′), 6.34 (m, 1 H, Ha-N-
3), 5.71 (s, 1 H, H-7), 5.28−4.39 (m, 6 H, H-4, H-5″, H-6″, H-7″, H-
8″, Ha-N-2), 5.00 (d, 1 H, H-1), 4.22 (m, 2 H, H-6), 4.08 (m, 1 H,
Hb-N-3), 3.70 (m, 1 H, H-5), 3.42−3.31 (m, 1 H, H-3), 3.35 (s, 3 H,
OCH3), 3.04−2.68, 2.51−2.31 (m, 6 H, H-2, H-1″, H-4″, Hb-N-2),
1.88−1.56 (m, 4 H, H-2″, H-3″) ppm. 13C NMR (75 MHz, acetone-
d6): δ 130.3 (C4′), 129.3 (C3′), 127.9 (C2′), 102.6 (C7), 100.5 (C1),
84.4, 82.2, 81.7, 80.8 (C5″, C6″, C7″, C8″), 73.7 (C4), 69.8 (C6), 63.0
(C5), 55.3 (OCH3), 54.1 (C2), 50.7 (C3), 26.6 (C1″, C4″), 22.0, 21.
Nine (C2″, C3″) ppm.
General Procedure for the Synthesis of Monocationic
Complexes by Means of Ammonium Hexafluoridophosphate.
Complex precursor 33b (47 mg, 0.076 mmol), ligand 28 (43 mg, 0.15
mmol), and ammonium hexafluoridophosphate (25 mg, 0.15 mmol)
were heated with stirring in methanol (15 mL) to reflux until a clear
solution was obtained (1 h). The solution was reduced to a few
milliliters (just after the start of precipitation) and cooled in a
refrigerator (−20 °C). The yellow precipitate of 43 (58 mg, 0.083
mmol; 54% yield) was washed with a few milliliters of cold methanol
and with diethyl ether and then dried under vacuum.
[T-4-R]-Chlorido(methyl 2,3-diamino-4,6-O-benzylidene-2,3-di-
deoxy-α-D-gulopyranoside)pentamethyl-η5-cyclopentadienyl-
rhodium(III) Hexafluoridophosphate (43). Orange-yellow powder.
[α](dichloromethane, 25 °C, 589 nm) = 135°. [α](acetone, 25 °C,
589 nm) = 75°. Anal. Found: C, 40.46; H, 5.06; N, 3.80. Calcd for
C24H37ClF6N2O5PRh (NMR: [C24H35ClN2O4Rh]PF6·H2O): C,
40.21; H, 5.20; N, 3.91; the compound contains 1 equiv of water.
HRMS (ESI): m/z 553.1352 (100%, [M]+, calcd 553.1340). 1H NMR
(300 MHz, CD2Cl2): δ 7.45−7.31 (m, 5 H, H-2′, H-3′, H-4′), 5.54 (s,
1 H, H-7), 4.93 (d, 1 H, H-1), 4.30−4.07 (m, 4 H, H-4, Ha-6, Hb-6,
H−N), 3.95 (m, 1 H, H-5), 3.64−3.50 (m, 5 H, H-3, H-7, H−N {3.51
[s, 3 H, OCH3]}), 3.47−3.38 (m, 2 H, H-2, H−N), 3.18 (m, 1 H, H−
N), 1.71 (s, 15 H, C5(CH3)5) ppm. 1H NMR (300 MHz, NCCD3): δ
7.45−7.31 (m, 5 H, H-2′, H-3′, H-4′), 5.63 (s, 1 H, H-7), 4.99 (d, 1 H,
H-1), 4.72 (m, 2 H, H−N-3), 4.60 (m, 1 H, Ha-N-2), 4.34−4.15 (m,
4-H, H-3, H-4, H-6), 4.11 (m, 1 H, H-5), 3.63−3.51 (m, 1 H, Hb-N-
2), 3.56 (s, 3 H, OCH3), 3.42 (m, 1 H, H-2), 1.80 (s, 15 H, C5(CH3)5)
ppm. 13C NMR (75 MHz, NCCD3): δ 129.4 (C4′), 128.6 (C3′),
126.7 (C2′), 101.2 (C7), 98.9 (C1), 75.5 (C4), 69.3 (C6), 58.9 (C5),
55.6, 55.3, 50.1 (C2, C3, OCH3), 9.0 (C5(CH3)5) ppm.
1
1.97, 1.75 (m, 4 H, H-2‴, H-3‴) ppm. H NMR (300 MHz, 1,1,2,2-
tetrachlorethane-d2): δ 7.66, 6.90 (AA′BB′, 4 H, H-2′, H-3′), 7.40−
7.23, 7.07 (m, 5 H, H-2″, H-3″, H-4″), 6.34 (s, 1 H, H−N-3), 5.63,
5.40 (m, 4 H, H-5‴, H-6‴, H-7‴, H-8‴), 5.38−5.30 (m, 1 H, H-3)
5.26 (s, 1 H, H-7), 5.00 (d, 1 H, H-1), 4.10 (dd, 1 H, Ha-6), 3.77−3.50
(m, 4 H, H-5, Hb-6, H−N-2), 3.36 (s, 3 H, OCH3), 3.41−2.93 (m, 2
H, H-2, H-4), 3.13−2.94, 2.51−2.28 (m, 4 H, H-1‴, H-4‴), 2.24 (s, 3
H, (CO)CH3), 2.06−1.91, 1.79−1.63 (m, 4 H, H-2‴, H-3‴) ppm. 13
C
NMR (shifts from HSQC, 1,1,2,2-tetrachlorethane-d2): δ 129.3, 127.3
(C2′, C3′), 127.9 (C3″), 126.5 (C2″), 101.8 (C7), 98.8 (C1), 83.4,
82.7, 79.4, 74.2 (C5‴, C6‴, C7‴, C8‴), 68.5 (C6), 63.6 (C5), 55.1
(OCH3), 26.5 (C1‴, C4‴), 21.7 ((CO)CH3), 21.3 (C2‴, C3‴) ppm.
Dichlorido-η1-(methyl 2-amino-4,6-O-benzylidene-2,3-dideoxy-3-
tosylamido-α-D-glucopyranoside)pentamethyl-η5-cyclopenta-
dienylrhodium(III) (52; 93% Yield). Orange powder. [α]-
(dichloromethane, 25 °C, 589 nm) = −11°. Anal. Found: C, 50.14;
H, 5.59; N, 3.88; S; 3.82. Calcd for C31H41Cl2N2O6RhS: C, 50.08; H,
1
5.56; N, 3.77; S, 4.31. H NMR (300 MHz, CD2Cl2): δ 7.63, 6.89
(AA′BB′, 4 H, H-9, H-10), 7.39−7.25, 7.08 (m, 5 H, H-15, H-16, H-
17), 6.18 (m, 1 H, H−N-3), 5.30 (s, 1 H, H-13), 5.13 (d, 1 H, H-1),
4.08 (dd, 1 H, Ha-6), 3.69−3.56 (m, 2 H, H-5, Hb-6), 3.53−3.41 (m,
4 H, H-3, H-4, H−N-2), 3.37 (s, 3 H, OCH3), 3.21 (dd, 1 H, H-2),
2.23 (s, 3 H, (CO)CH3), 1.71 (s, 15 H, H-18) ppm. 13C NMR (75
MHz, CD2Cl2): δ 129.2, 127.4 (C2′, C3′), 128.7 (C4″), 127.8 (C3″),
126.3 (C2″), 101.7 (C7), 98.5 (C1), 78.4 (C4), 68.5 (C6), 63.8 (C5),
56.5 (C2), 55.6 (C3), 54.6 (OCH3), 21.3 ((CO)CH3), 9.0
(C5(CH3)5) ppm.
[T-4-R]-Chlorido(methyl 2,3-diamino-4,6-O-benzylidene-2,3-di-
deoxy-α-D-gulopyranoside)-η6 -(1″,2″,3″,4″-tetrahydro-
naphthalene)ruthenium(II) Hexafluoridophosphate (45; 94% Yield).
Yellow powder. [α](acetone, 25 °C, 589 nm) = 133°. [α](dimethyl
sulfoxide, 25 °C, 589 nm) = 115°. Anal. Found: C, 41.64; H, 4.69; N,
ASSOCIATED CONTENT
■
S
* Supporting Information
1
3.94. Calcd for C24H32ClF6N2O4PRu: C, 41.54; H, 4.65; N, 4.04. H
Text, tables, figures, and CIF and xyz files giving crystallo-
graphic data for 18, 25, 26, 32, 34, 35, 39, 42 and 46, molecular
structures of 18 and 31, crystal packing of 35, 39, 42, and 46,
synthesis of the organic compounds, additional NMR
spectroscopic data of the complexes, T/C values from primary
screening of the complexes, molecular structures of 10, 19, 28,
29 and 32, and data derived from DFT calculations. This
NMR (300 MHz, NCCD3): δ 7.43−7.30 (m, 5 H, H-2′, H-3′, H-4′),
6.18 (m, 1 H, Ha-N-2), 5.87 (m, 1 H, Ha-N-3), 5.81−5.45 (m, 5 H, H-
7, H-5″, H-6″, H-7″, H-8″), 4.91 (d, 1 H, H-1), 4.67 (m, 1 H, Hb-N-
3), 4.30 (dd, 1 H, H-4), 4.21 (m, 2 H, H-6), 4.10−3.99 (m, 2 H, H-5,
Hb-N-2 {4.03 [m, 1 H, H-5]}), 3.55 (s, 3 H, OCH3), 3.31 (m, 1 H, H-
2), 3.15 (m, 1 H, H-3), 2.98−2.77, 2.68−2.50 (m, 4 H, H-1″, H-4″),
1.94−1.66 (m, 4 H, H-2″, H-3″) ppm. 1H NMR (300 MHz, dmso-d6):
1519
DOI: 10.1021/om5013117
Organometallics 2015, 34, 1507−1521

Organometallics
Article
7562−7563. (g) Inoue, Sh.; Nomura, K.; Hashiguchi, S.; Noyori, R.;
Izawa, Y. Chem. Lett. 1997, 957−958.
material is available free of charge via the Internet at http://
pubs.acs.org.
(10) (a) Rosenberg, B.; van Camp, L.; Krigas, T. Nature 1965, 205,
698−699. (b) Rosenberg, B.; van Camp, L. Nature 1969, 222, 385−
386.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail for J.H.: juergen.heck@chemie.uni-hamburg.de.
(11) (a) Murphy, D. Chem. Ind. 1966, 37, 1555. (b) Hartinger, C. G.;
Nazarov, A. A.; Ashraf, S. M.; Dyson, P. J.; Keppler, B. K. Curr. Med.
Chem. 2008, 15, 2574−2591. (c) Yano, S.; Mikata, Y. Bull. Chem. Soc.
Notes
Jpn. 2002, 75, 2097−2113. (d) Moker, J.; Thiem, J. Eur. J. Org. Chem.
̈
The authors declare no competing financial interest.
2009, 4842−4847.
(12) Reddy, V. D.; Dayal, D.; Cosenza, S. C.; Ramana Reddy, M. V.;
Pearl, W. C., Jr.; Adams, R. D. J. Organomet. Chem. 2009, 694, 959−
967.
ACKNOWLEDGMENTS
■
This paper is dedicated to Prof. Dr. Uwe Rosenthal on the
occasion of his 65th birthday. We thank Prof. Dr. Ulrich
Behrens for supporting the solution of the crystallographic data
sets, the X-ray section of Dr. Frank Hoffmann and the NMR
spectroscopy section of Dr. Eckhardt Haupt for the measure-
ments.
(13) (a) Gras, M.; Therrien, B.; Suss-Fink, G.; Casini, A.; Edafe, F.;
̈
Dyson, P. J. J. Organomet. Chem. 2010, 695, 1119−1125. (b) Nazif, M.
A.; Rubbiani, R.; Alborzinia, H.; Kitanovic, I.; Wolfl, S.; Ott, I.;
̈
Sheldrick, W. S. Dalton Trans. 2012, 41, 5587−5598. (c) Novohradsky,
V.; Zerzankova, L.; Stepankova, J.; Kisova, A.; Kostrhunova, H.; Liu,
Z.; Sadler, P. J.; Kasparkova, J.; Brabec, V. Metallomics 2014, 6, 1491−
1501. (d) Casini, A.; Edafe, F.; Erlandsson, M.; Gonsalvi, L.; Ciancetta,
A.; Re, N.; Lenco, A.; Messori, L.; Peruzzini, M.; Dyson, P. J. J. Chem.
Soc., Dalton Trans. 2010, 39, 5556−5563. (e) Betanzos-Lara, S.;
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