An innovative and efficient route to the synthesis of metal-based glycoconjugates: proof-of-concept and potential applications

Article abstract of DOI:10.1039/c8dt01583j

With a view to developing more efficient strategies to the functionalization of metallodrugs with carbohydrates, we here report on an innovative and efficient synthetic route to generate gold(iii) glycoconjugates in high yields and purity. The method is based on the initial synthesis of the zinc(ii)-dithiocarbamato intermediate [Zn^II(SSC-Inp-GlcN)₂] (Inp = isonipecotic moiety; GlcN = amino-glucose) followed by the transfer of the glucoseisonipecoticdithiocarbamato ligand to the gold(iii) center via transmetallation reaction between the zinc(ii) intermediate and K[Au^IIIBr₄] in 1?:?2 stoichiometric ratio, yielding the corresponding glucose-functionalized gold(iii)-dithiocarbamato derivative [Au^IIIBr₂(SSC-Inp-GlcN)]. No protection/deprotection of the amino-glucose scaffold and no chromatographic purification were needed. The synthetic protocol was optimized for glucose precursors bearing the amino function at either the C² or the C⁶ position, and works in the case of both α and β anomers. The application of the synthetic strategy was also successfully extended to other metal ions of biomedical interest, such as gold(i) and platinum(ii), to obtain [Au^I(SSC-Inp-GlcN)(PPh₃)] and [Pt^II(SSC-Inp-GlcN)₂], respectively. All compounds were fully characterized by elemental analysis, mid- and far-IR, mono- and multidimensional NMR spectroscopy, and, where possible, X-ray crystallography. Results and potential applications are here discussed.

Full text of DOI:10.1039/c8dt01583j

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Joseph T. Hupp, Omar K. Farha et al.
Efficient extraction of sulfate from water using
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ARTICLE
An innovative and efficient route to the synthesis of metal-based
glycoconjugates: proof-of-concept and potential applications†
Andrea Pettenuzzo, a Diego Montagner, b Patrick McArdle a and Luca Ronconi*a
Received
Accepted
DOI: 10.1039/x0xx00000x
www.rsc.org/
With a view to developing more efficient strategies to the functionalization of metallodrugs with carbohydrates, we here
report on an innovative and efficient synthetic route to generate gold(III) glycoconjugates in high yields and purity. The
method is based on the initial synthesis of the zinc(II)-dithiocarbamato intermediate [ZnII(SSC-Inp-GlcN)2] (Inp
=
isonipecotic moiety; GlcN = amino-glucose) followed by the transfer of the glucoseisonipecoticdithiocarbamato ligand to
the gold(III) center via transmetallation reaction between the zinc(II) intermediate and K[AuIIIBr4] in 1:2 stoichiometric
ratio, yielding the corresponding glucose-functionalized gold(III)-dithiocarbamato derivative [AuIIIBr2(SSC-Inp-GlcN)]. No
protection/deprotection of the amino-glucose scaffold and no chromatographic purification were needed. The synthetic
protocol was optimized for glucose precursors bearing the amino function at either the C2 or the C6 position, and works in
the case of both α and β anomers. The application of the synthetic strategy was also successfully extended to other metal
ions of biomedical interest, such as gold(I) and platinum(II), to obtain [AuI(SSC-Inp-GlcN)(PPh3)] and [PtII(SSC-Inp-GlcN)2],
respectively. All compounds were fully characterized by elemental analysis, mid- and far-IR, mono- and multidimensional
NMR spectroscopy, and, where possible, X-ray crystallography. Results and potential applications are here discussed.
several carbohydrate-derived or -containing drugs are
marketed, e.g. zanamivir (antiviral), acarbose (antidiabetic),
heparin and fondaparinux (anticoagulant), doxorubicin
Introduction
Research aimed at designing novel synthetic carbohydrate
derivatives has been steadily expanding over the last two
decades owing to their potential biomedical applications.1
Glycosylation (that is, the biochemical process by which a
carbohydrate is covalently bound to the target biomolecule
such as proteins and lipids) is involved in many metabolic
events and affects a number of cellular processes, including
(anticancer), epoetin alfa and darbepoetin alfa (anemia
treatment), hiberix (haemophilus
B conjugate vaccine),
menjugate (meningitis C vaccine),4 and many more are
currently under pre-clinical and clinical trials.5
Within the field of chemotherapy, conjugation of anticancer
drugs to biomolecules has been successfully achieved in recent
years by developing, for example, antibody-drug6 and folate-
drug7 conjugates which are currently in clinical use.
Intriguingly, compared with peptides, synthetic carbohydrates
proved challenging to be obtained, mainly due to the
complexity of the traditional synthesis in solution. In
particular, difficulties associated with stereoselective glycosidic
bond formation and the extensive use of protecting groups
(and subsequent selective deprotection),8 resulted in lengthy
multi-step syntheses requiring several purifications of the
various intermediate products by column chromatography
and, ultimately, affording poor overall yields.9 The exploitation
and optimization of alternative synthetic approaches, such as
chemoenzymatic,10 automated solid-phase,11 and microwave-
assisted12 synthesis, have substantially boosted the field in
terms of shorter reaction times and higher yields. On the other
hand, such techniques are not always exploitable for all
glycoconjugates, especially when the carbohydrate
functionalization is applied to metal-containing substrates.
cell
proliferation
and
differentiation,
intercellular
communications, and carbohydrate-mediated recognition
processes such as the immune response.2 Therefore, given the
crucial biological role played by carbohydrates, it is not
surprising that research in glycoscience has strong implications
for biotechnology and medicine in order to develop new
therapeutic agents for the treatment of various diseases.
Glycoconjugation (that is, the functionalization of drugs with
glucose or other carbohydrates) is currently under intense
investigation, and applications include: carbohydrate-based
drugs and vaccines, adjuvants, metabolic labelling of glyco-
structures, and glycan arrays for diagnostic purposes.3 To date,
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Owing to the potentiality of metallodrugs, the latest Rationale
approaches focus on the functionalization of metal-based
In terms of medicinal applications, glycoconjugation can be
exploited to achieve the specific targeting and treatment of
cancer.17 This strategy relies on the evidence that rapidly
dividing tumor cells require higher amounts of nutrients and
energy to sustain their fast proliferation, including especially
glucose. In fact, glucose uptake proved to be 10 to 12-fold
higher in tumors compared with healthy tissues, and glucose
transporters (GLUTs), devoted to the recognition and cellular
internalization of glucose, are largely overexpressed in tumor
cells, thus indicating their strong dependence on such
transporters for their survival and growth.18 The fact that
anaerobic glycolysis is the major glucose metabolism in tumors
is a phenomenon called “the Warburg effect” (named after the
German biochemist Otto Warburg who first observed it),19 and
it is acknowledged nowadays as one of the hallmarks of
cancer.20 Consequently, such increased demand of glucose by
cancer cells makes it very attractive to selectively target tumor
sites. In particular, tailored glucose-like substrates can be
conjugated to chemotherapeutics to attain the site-specific
delivery of drugs into the affected tissues (i.e. targeted
anticancer chemotherapy and tumor imaging).21 This approach
was especially inspired by the evidence that the clinically-
established positron emission tomography (PET) tracer [18F]-
fluorodeoxyglucose is preferentially taken up by cancer cells
compared with normal tissues,22 and has been recently
extended to the design of carbohydrate-based nanocarriers.23
As previously pointed out, the complexity of carbohydrate
chemistry may severely hamper glycoconjugation of drugs, in
particular when metal-based scaffolds are involved. Therefore
more efficient synthetic approaches to glyco-functionalization
are required. As shown in Scheme 1, our suggested strategy
relies on the pre-generation of a zinc(II)-dithiocarbamato
glycoconjugate precursor followed by the transfer of the
whole dithiocarbamato ligand to the desired metal center
scaffolds with biologically-active ligands having tumor
targeting properties (i.e. carriers), thereby maximizing the
therapeutic outcomes on cancer cells and minimizing the
occurrence of side-effects.13
A
number of metal
glycoconjugates have been reported to date,14a,b especially
glucose derivatives in which conjugation occurs mainly at the
anomeric C1 position.14c-f Nevertheless, in most cases
coordination of glucose-like substrates to metal centers
proved somewhat demanding and involved several steps. For
example, Lippard and co-workers have recently reported on
the synthesis of all possible positional isomers (C1α, C1β, C2, C3,
C4 and C6) of a glucose-oxaliplatin conjugate.15 Remarkably,
each isomer required 4-12 steps with yields of 15-30%
(considering only the final step leading to the corresponding
platinum(II) glycoconjugate).
On the basis of the aforementioned considerations, given our
well-established expertise in the development of gold(III)-
dithiocarbamato complexes,16 we here report on an
innovative, facile and efficient synthetic route to the
generation of gold(III)-dithiocarbamato glycoconjugates. Our
strategy relies on the one-pot synthesis of
a bis-
dithiocarbamato-zinc(II) intermediate which can be
subsequently functionalized with an amino-glucose moiety.
The desired glucosedithiocarbamato ligand is then transferred
to the gold(III) metal center via
a
zinc(II)-gold(III)
transmetallation reaction yielding the corresponding high
purity gold(III)-dithiocarbamato glycoconjugate in excellent
yields (70-90%) (Scheme 1). Remarkably, neither
protection/deprotection of the amino-glucose scaffold nor
chromatographic purification were required, and the
transmetallation reactions reached completion within a few
hours.
In order to assess the potential of this synthetic protocol to
other metal ions, we applied the same procedure also to
gold(I) and platinum(II), and succeeded in generating the
corresponding glycoconjugates.
through
a
transmetallation reaction. Specifically, we
developed a facile and reproducible protocol in which an
amino acidic linker is functionalized with the dithiocarbamato
Experimental details and results are here discussed and
compared with the synthetic strategies currently available in
the literature.
moiety
(−NCSS) at the amino terminus, whereas the
carboxylate tail is first activated and then conjugated to an
amino-sugar. The rationale of this strategy is based on the
following considerations.
Results and Discussion
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•
Dithiocarbamates are versatile monoanionic ligands
capable of stabilizing a wide range of metal ions by
coordinating the metal center in either monodentate or
chelating bidentate modes.24 Although referred to as “soft”
Lewis bases (and, thus, expected to coordinate mainly
“soft” Lewis acids such as low-valent metal ions), they may
be also regarded as “hard” ligands in the thioureide
resonance form (Scheme 2), which favors the binding of
metals in higher oxidation states (i.e. “hard” Lewis acids).25
led to the reduction of gold(III) to gold(I) and the
simultaneous degradation of the carbohydrate scaffold
resulting from the intramolecular attack of the
group located in the C2 position of the glucose to the
anomeric site (data not shown).34
−NCSS
•
The use of an amino acidic linker between the
dithiocarbamato function and the conjugated sugar has a
two-fold purpose. From a practical synthetic point of view
it allows the straightforward conversion of the amino
terminus into an
−
NCSS group35 without worrying about
the possible side-reactions involving the carbohydrate
scaffold, should the latter be present. On the other hand,
the carboxylic function can be easily activated with
N,N,Nˈ,Nˈ-tetramethyl-O-(N-succinimidyl)uronium (TSTU)
and subsequently coupled to an amino-sugar to attain
glycoconjugation through the formation of an amide
bond.36
Scheme 2 Resonance forms of the dithiocarbamato ligands.
Accordingly, dithiocarbamates can be used to coordinate a
number of metal ions in different oxidation states affording
stable complexes.26
Moreover, from a biological perspective, if the final goal is
to target the GLUTs overexpressed in tumors to achieve
selectivity, the anomeric position of the glucose-like unit
should be sufficiently accessible to be recognized (and,
thus, internalized inside the tumor cell) by such
transporters.21a Therefore, the inclusion of a rigid linker
(like the isonipecotic moiety used in this work) would
reduce the steric hindrance around the anomeric site of
the sugar, thus allowing, at least in principle, its recognition
by GLUTs.
•
An added value of using dithiocarbamato ligands is that,
once coordinated to a bioactive metal center, they may act
as intrinsic chemoprotectants against the toxicity of metal-
based drugs, thus reducing their side-effects.27
Consequently, not only metal-dithiocarbamato derivatives
have been largely explored in recent years as potential
anticancer agents,25 but the chemoprotective activity of
the dithiocarbamato moiety has been confirmed in vivo, in
particular for gold(III) derivatives.28
•
Dithiocarbamates of primary and secondary amines are
generally synthesized by reaction with carbon disulfide
(CS2) under basic conditions (e.g. NaOH, KOH, Et3N) at low
temperature, yielding the corresponding dithiocarbamato
salts.29 Dithiocarbamates generated from primary amines
are often unstable and tend to decompose to give the
corresponding isothiocyanates.30 The secondary amine
counterparts are generally more stable and a number of
simple dithiocarbamates have been prepared and isolated
as sodium or ammonium salts.31 Nevertheless, isolation
and storage of free dithiocarbamates is often challenging
since, at room temperature, they may decompose back to
the starting amine and CS2, especially under acidic
conditions.32 For this reason, dithiocarbamates are best
prepared in situ: once generated in solution they are
reacted with the metal precursor in the appropriate
stoichiometric ratio to obtain the corresponding metal-
dithiocarbamato derivative.25
Model non-glycosylated gold(III)-dithiocarbamato complexes
Taking into account the aforementioned issues, we first
evaluated the feasibility of our synthetic approach by
generating
non-glycosylated
gold(III)-dithiocarbamato
complexes via transmetallation from the corresponding zinc(II)
intermediates (Scheme 3). Specifically, we focused on ethyl
isonipecotate (Inp-OEt) and isonipecotamide (Inp-NH2)
dithiocarbamates as model ligands since their amino group is a
symmetric secondary amine and, as such, can lead to very
stable, symmetric compounds.26
In principle, direct functionalization of an amino-sugar
could be achieved. To the best of our knowledge, only one
of such example is reported in the literature. Zhang and co-
workers
synthesized
and
isolated
2-deoxy-2-
dithiocarbamato-
D
-glucose as sodium salt by reacting D-
glucosamine hydrochloride with CS2 and NaOH, and used it
to obtain the corresponding 99mTc-nitrido bis-
dithiocarbamato complex.33 Unfortunately, when following
the same experimental procedure, we could not obtain the
analogous gold(III) complex. Notwithstanding various
attempts, the experimental conditions employed always
Figure 1 X-ray crystal structure with atom numbering scheme
for Na(SSC-Inp-NH2) (CCDC 1835869) (50% displacement
ellipsoids).
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O
O
S
S
1) CS2 (1 eq.), H2O/EtOH, 0°C, 3 h
Zn
N
OCH2CH3
HN
OCH2CH3
2) ZnCl2 (0.25 eq.), H2O, r.t.
H
H
2
[ZnII(SSC-Inp-OEt)2] (Zn1)
O
S
1) 16 h
2) [Zn(OAc)2] (0.5 eq.), H2O, r.t.
Zn
N
NH2
H
S
2
O
[ZnII(SSC-Inp-NH2)2] (Zn2)
CS2 (2 eq.), NaOH (1 eq), MeOH, 0°C
HN
NH2
H
O
S
S
1) 3 h
[Zn(OAc)2] (0.5 eq), H2O, r.t.
Na
N
NH2
2) CS2 (1 eq.), 4°C, 16 h
H
Na(SSC-Inp-NH2)
O
O
2' 3'
2' 3'
1' 4'
S
Br
Br
S
S
K[AuBr4] (2 eq.), DMF, r.t, 1-3 h
1' 4'
6' 5'
Au
Zn
N
R
N
R
H
H
S
2
6' 5'
R = OCH2CH3 (Zn1)
R = NH2 (Zn2)
R = OCH2CH3 (Au1)
R = NH2 (Au2)
Scheme 3 Synthesis of the model (i.e. non-glycosylated) gold(III)-dithiocarbamato derivatives via transmetallation.
Amongst our numerous initial attempts to isolate free
dithiocarbamates, we succeeded in obtaining only one, that is,
ν(N−CSS) is recorded at higher frequencies (1571 (Au1)/1565
(
Au2) cm-1) due to the increased electron-withdrawing effect
isonipecotamidedithiocarbamate as sodium salt (Na(SSC-Inp- upon moving from zinc(II) to the more positively charged
NH2), Figure 1; see the ESI for details).
Both [ZnII(SSC-Inp-OEt)2] (Zn1) and [ZnII(SSC-Inp-NH2)2] (Zn2
gold(III) center, suggesting a greater contribution of the
“thioureide” resonance form (Scheme 2).41 Additionally, the
)
were obtained in a one-pot reaction. Zn2 was obtained also by detection of a single band at ca. 1000 cm-1 in all complexes
reacting the free ligand Na(SSC-Inp-NH2) with [ZnII(OAc)2] in (attributed to the
2:1 ratio. bidentate coordination of the
Zinc(II) is a “borderline” Lewis acid37 and, although it forms centers, in agreement with the Bonati-Ugo criterion.42
stable covalent adducts with the “soft” dithiocarbamato In the far-IR spectra of a number of metal-dithiocarbamato
ligands,26 it is well-known to serve as a source of such ligands complexes, bands recorded in the range 420-320 cm-1 are
νa(SCS)) clearly supports a symmetrical
−
NCSS moiety to the metal
for
a softer metal (possibly much more reliable and regarded as highly diagnostic since they are assigned to the
controllable than the commonly employed ionic sodium, metal-sulfur stretching vibrations. Zn1 and Zn2 show an
potassium or ammonium dithiocarbamato salts).38 Therefore, intense absorption at ca. 395 cm-1 originating from the
zinc(II) dithiocarbamates may undergo transmetallation
ν
a(ZnS4),43 whereas the corresponding symmetric stretching is
reactions with many “soft” transition metals, including absent as it is not IR-active in the tetrahedral bis-
gold(III).39 In this regard, the zinc(II)-gold(III) transmetallation dithiocarbamato zinc derivatives.44 On the contrary, both
reaction was optimized in DMF, yielding the gold(III)
counterparts [AuIIIBr2(SSC-Inp-OEt)] (Au1) and [AuIIIBr2(SSC- complexes (at 413/398 and 411/397 cm-1, respectively), in
Inp-NH2)] (Au2) in high yields (>70%) and no need of further agreement with those reported in the literature for similar
νa,s(SAuS) are recorded for the square-planar Au1 and Au2
purification.
gold(III)-dithiocarbamates.45 Finally, other informative bands
IR spectroscopy proved useful to identify the synthesized are observed at lower frequencies for the latter complexes at
compounds. By comparison with the spectra recorded for the 249/228 (Au1) and 232/227 (Au2) cm-1, attributed to the
starting ethyl isonipecotate and isonipecotamide reagents (see
the ESI for details), the appearance of a strong band at 1494 Mono- and multinuclear NMR spectroscopy provided further
Zn1)/1492 (Zn2) cm-1 in the zinc(II) derivatives (the so-called insights into the identification of the dithiocarbamato
ν
a,s(BrAuBr) for terminal cis-bromides.46
(
“thioureide” band,
dithiocarbamato ligand coordinated to a zinc(II) center.40 isonipecotate reagent, a general downfield shift of the proton
When taking into account the gold(III) counterparts, the signals is observed for the zinc(II) intermediate Zn1 and the
ν(N−CSS)) is consistent with a chelating complexes. For example, compared with the starting ethyl
4 | Dalton Trans., 20xx, xx, x-x
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corresponding transmetallation product Au1 (Figure 2). This is complexes are known, which have highly strained structures
consistent with the decreased electron density experienced by with two four-membered rings,51 a common arrangement for
the hydrogen atoms of the isonipecotate scaffold upon this class of compounds is dinuclear centrosymmetric,52 and
introducing the dithiocarbamato moiety and the subsequent this was observed also for Zn1. Dimeric structures, in which
coordination to the metal centers, the gold(III) ion exerting one four-membered zinc(II)-dithiocarbamato ring is retained
greater deshielding than zinc(II) due to the higher oxidation whereas the other has opened to form an eight-membered
state.47 As expected, the larger shift involves the piperidine ring, were first reported for the bis-diethyldithiocarbamato-
hydrogens, the only partial exception to this trend being the zinc(II) complex,53 and have since been reported for several
C
2ˈ,6ˈH equatorial protons which undergo a 0.7 ppm upfield other analogous derivatives.54 Relief of distortion is the most
shift in Au1 with respect to Zn1. On moving away from the likely reason for the adoption of the dimeric structure, and the
dithiocarbamato moiety, the magnitude of the chemical shift angle at the zinc(II) center in the four-membered ring is
change decreases until being negligible for the farther ester 75.79(4)°.
group.
Figure 3 X-ray crystal structure with atom numbering scheme
for Zn1 (CCDC 1835870) and Au1 (CCDC 1835871) (50%
Figure 2 Comparison of the 1H NMR spectra in DMSO-D6 of
ethyl isonipecotate, [ZnII(SSC-Inp-OEt)2] (Zn1) and [AuIIIBr2(SSC-
displacement ellipsoids).
Inp-OEt)] (Au1).
As to the crystal structure of Au1, there is distortion from
square-planar geometry due to the small bite angle of the
dithiocarbamato ligand. However, there the maximum
deviation from the least-squares plane defined by the gold(III)
center and the ligating atoms of 0.008 Å is shown by S1 and S2.
The bond distances are in the range previously reported and
are close to those found in other dibromo-dithiocarbamato-
The most diagnostic peak recorded in the 13C{1H} NMR spectra
is attributed to the dithiocarbamic carbon atom and is
generally found in the range 180-220 ppm.48 It is generally
assumed that the 13C chemical shifts of the
−NCSS moiety are
strongly dependent on both the type of metal-dithiocarbamate
bonding and the oxidation state of the metal center. As to the
dithiocarbamato complexes of transition metals owning a d10
gold(III)
dithiocarbamato complex Zn1 has Zn
four-membered rings which differ by a near constant 0.1 Å,
whereas in the gold(III) counterpart Au1 the Au S distances
complexes.55,56a
Interestingly,
the
zinc(II)-
−
S distances within the
electron configuration (such as zinc(II)), the δ
(N13CSS) peaks
are recorded in the range 202-206 ppm,49 whereas for
derivatives of high oxidation state transition metals (such as
gold(III)), the dithiocarbamic carbon signals appear upfield.50
−
have differences which are ten times smaller. Further details
of the structures are provided in the ESI.
There is a strong empirical correlation between
δ
(N13CSS)
CSS stretching vibrations in the infrared
(N CSS) values indicate an increased
Analogous gold(III)-dithiocarbamato complexes have been
previously obtained through one-pot template reactions,41,56
invariably resulting in a mixture of two forms (whose relative
abundance varies depending on the synthetic conditions), that
is, the expected gold(III) derivative and a dimeric form in which
two bridging dithiocarbamato ligands are bound to both
gold(III) centers whose coordination sphere is completed by
two trans-bromide moieties.57 Remarkably, our zinc(II)-gold(III)
transmetallation strategy led to the generation of the
expected monomeric form only.
values and the N
spectra: higher
−
ν
−
carbon
with lower
density on the
these considerations are fully consistent with the experimental
(N
CSS) frequencies and the N13CSS carbon signals recorded
for the object dithiocarbamato complexes (202.6 (Zn1), 202.3
Zn2), 187.9 (Au1) and 186.9 (Au2) ppm).
−
nitrogen double bond character, which well correlates
(N13CSS) values because of a greater electron
NCSS moiety, and the other way round.48 All
δ
−
ν
−
(
Crystals suitable for X-ray diffraction crystallography were
obtained for Zn1 and Au1 (Figure 3). Although crystal
Gold(III)-dithiocarbamato glycoconjugates
structures
of
monomeric
bis-dithiocarbamato-zinc(II)
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O
N
O
O
O
S
S
S
S
(a)
(b)
(c)
Na2 Zn
N
O
2H2O
Zn
N
O
H2N
O
H
H
H
2
O
2
Na2[ZnII(SSC-Inp-O)2].2H2O (Zn0a)
[ZnII(SSC-Inp-OSu)2] (Zn0b)
(d)
(e)
(f)
OH
OH
O
6
3
6
4
HO
HO
4
2' 3'
O
O
5
5
S
HO
HO
1
1
N1' 4'
NH
OH
OCH3
2
2
H
S
3
NH
NH
6' 5'
6
4
2' 3'
2' 3'
O
5
S
S
S
S
HO
HO
1
Zn
N1' 4'
O
Zn
N1' 4'
O
2
H
H
3
OH
OCH3
6' 5'
6' 5'
2
2
2
[ZnII(SSC-Inp-GlcN1)2] (Zn3)
[ZnII(SSC-Inp-GlcN2)2] (Zn4)
[ZnII(SSC-Inp-GlcN3)2] (Zn5)
(a) CS2 (1 eq.), NaOH (2 eq.), MeOH, 0°C, 6 h; (b) [Zn(OAC)2].2H2O (0.5 eq.), MeOH, r.t.; (c) TSTU (2.2 eq.), DIPEA (0.2 eq.), anhyd. DMF, r.t., N2, 16 h;
(d) (GlcN1).HCl (2.5 eq), DIPEA (7.5 eq.), anhyd. DMF, r.t., N2, 16 h; (e) (GlcN2)(CH3COOH) (2.4 eq), DIPEA (1 eq.), anhyd. DMF, r.t., N2, 16 h; (f)
(GlcN3) (2.5 eq), DIPEA (5.5 eq.), anhyd. DMF, r.t., N2, 16 h.
NH2
OH
OH
O
O
O
HO
HO
HO
HO
HO
HO
OH
OCH3
OH
NH2
NH2
OCH3
(GlcN1)
(GlcN2)
(GlcN3)
Scheme 4 Synthesis of the zinc(II)-dithiocarbamato glycoconjugate precursors.
Following the successful generation of the model non- As far as the amino-sugar substrates are concerned, we chose
glycosylated gold(III)-dithiocarbamato complexes, we applied three different glucose-like scaffolds (see the ESI for details on
the same synthetic strategy to obtain the corresponding syntheses and characterizations).
glycoconjugate counterparts. With reference to Scheme 4, we
first prepared the zinc(II)-dithiocarbamato derivative of
•
2-Amino-2-deoxy-(α,β)-D-glucose (aka (α,β)-D-glucosamine,
GlcN1) hydrochloride, bearing the amino function in the C2
isonipecotic acid, Na2[ZnII(SSC-Inp-O)2]∙2H2O
(
Zn0a), by
position of the glucose, is commercially available and is
optimizing a literature procedure.58 In order to conjugate the
amino-sugars to the isonipecotic linker, the carboxylic
functions of Zn0a were subsequently activated by converting
them into the corresponding succinimidyl ester, [ZnII(SSC-Inp-
OSu)2] (Zn0b). Although this is a well-known process, common
synthetic routes involve the use of acidic media in which
dithiocarbamates tend to decompose.32 Therefore, we
exploited the method reported by Suades and co-workers
which makes use of the peptide coupling reagent N,N,Nˈ,Nˈ-
sold as a mixture of α and β anomers (the former largely
predominating). Glucosamine-appended ligands have been
already used in some cases to obtain metal-
glycoconjugates.21b,c
•
1-O-methyl-2-amino-2-deoxy-(
α
GlcN2) was prepared as ammonium acetate according to a
,
β
)-
D
-glucopyranoside
(
literature procedure.59 An
α
:β
anomers ratio of
approximately 5:1 was obtained. Methylation of the
anomeric hydroxyl group (C1 position) aimed at avoiding
side-reactions involving the anomeric carbon in the
subsequent steps, as well as at simplifying the NMR
characterization of the final products.
tetramethyl-O-(N-succinimidyl)uronium
tetrafluoroborate
(TSTU) in presence of N,N-diisopropylethylamine (DIPEA).52
This procedure proved very efficient and straightforward also
because Zn0b could be easily isolated from the DMF reaction
medium by simple precipitation after addition of a 1:1
water/ethanol mixture. Both Zn0a and Zn0b were obtained in
high yield (68% and 93%, respectively) and purity, and their
spectroscopic characterization was fully consistent with
literature data.52
•
1-O-methyl-6-amino-6-deoxy-α-D-glucopyranoside (GlcN3)
was prepared according to a literature procedure60 with
the aim of investigating the feasibility of our synthetic
method for amino-sugars bearing the amino function in
positions other than the C2 site of the glucose (i.e. C6
position).
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An excess of each amino-sugar (2.4-2.5 eq.) was reacted with Inp-GlcN2)] (Au4) and [AuIIIBr2(SSC-Inp-GlcN3)] (Au5) (Scheme
the activated zinc(II) precursor Zn0b in anhydrous DMF under 5) in high yields (>75%) and no need of further purification.
basic conditions (DIPEA), leading to the coupling of the amino The synthesized gold(III) complexes were characterized by the
function of the glucose-like unit to the carboxylic group of the usual analytical and spectroscopic techniques. In the mid-IR
isonipecotic moiety, thus resulting in the formation an amide spectra the ν(N−CSS) band shifted from ∼1490 to ∼
1560 cm-1,
bond and the generation of the corresponding complexes as a result of the increased electron-withdrawing effect in the
[ZnII(SSC-Inp-GlcN1)2] (Zn3), [ZnII(SSC-Inp-GlcN2)2] (Zn4) and gold(III) derivatives compared with the zinc(II) counterparts,
[ZnII(SSC-Inp-GlcN3)2] (Zn5) (Scheme 4).
whereas in the far-IR spectra the absorptions at
∼
370 cm-1
By comparing the spectroscopic features of the starting
(
ν
a(ZnS4)) disappeared and new bands at 410/390 (νa,s(SAuS))
∼
reagents with those of the zinc(II)-dithiocarbamato and ∼
glycoconjugates, the most affected signals were those related consistent
245/225 (
ν
with
a,s(BrAuBr)) cm-1 were recorded instead,
the
expected
dibromide-gold(III)-
to the atoms in close proximity to the newly formed amide dithiocarbamato scaffold.
bond. In the IR spectra of Zn3-Zn5 the absorption bands In line with what is observed for the model non-glycosylated
originating from both the succinimidyl fragment of Zn0b complexes (see above), when moving from the zinc(II) to the
(
ν
ip(C=O succinimidyl),
at 1817, 1780 and 1737 cm-1)52 and from the were detected for the signals associated with the
amino/ammonium group of the sugar substrates GlcN1-GlcN3 isonipecoticdithiocarbamato fragments. comparative
(NH2) at example is given in Figure 4 for Au5. Remarkably, as a general
νoop(C=O succinimidyl) and ν(C=O ester) gold(III) glycoconjugates, major changes in the NMR spectra
A
+
+
+
+
(
ν
a(NH3 ),
3090, 2840, 1620, 1580, 3260 and 1600 cm-1, respectively)61 trend, the H signals recorded for the glucose hydroxyl groups
1640 ( (C=O, are properly resolved only for the zinc(II) intermediates,
ip(CNH, amide II)) cm-1 were detected,62 whereas for both the starting amino-sugars and the
νs(NH3 ), δa(NH3 ), δs(NH3 ), ν(NH2) and δ
1
∼
disappeared. Instead, new intense bands at
∼
ν
amide I)) and 1550 (
∼
δ
consistent with the replacement of the succinimidyl ester corresponding gold(III) derivatives peaks tend to collapse into
located in the same position by an amide group. On the a single very broad band (Figure 5A).
contrary,
substantially unchanged (at
respectively) compared with Zn0b. Analogously, the 1H and glucosamine (GlcN1). On the contrary, the percent of the
ν
(N
−
CSS),
ν
a(SCS),
ν
s(SCS) and
ν
a(ZnS4) remained In terms of the reactivity of the different anomers, the
α
to
β
∼
1490, 1000, 570 and 370 cm-1, ratio was substantially retained when using
(
α
,
β
)-
D
-
α
13C{1H} NMR signals corresponding to the zinc(II)- anomer dramatically increased by moving from O-methyl-2-
dithiocarbamato isonipecotic fragment and the glucose moiety amino-2-deoxy-
D-glucopyranoside (GlcN2, α:β ≈ 5:1) to the
recorded for Zn3-Zn5 were observed at chemical shifts similar corresponding zinc(II)-dithiocarbamato glycoconjugate (Zn4
,
to those found for the starting reagents, except the peaks
associated with the C4ˈH group of the piperidine ring, and the gold(III) analogue (Au4). This was assessed by measuring the
C2H group (for Zn3 and Zn4) or the C6H2 group (for Zn5) of the 3J(C1H,C2H) coupling constants in the 1H NMR spectra which
α:β ≈ 25:1), the β anomer being completely absent in the
glucose unit.
Eventually, zinc(II)-gold(III) transmetallation was achieved by respectively.63
reacting the zinc(II) precursors Zn3-Zn5 with K[AuIIIBr4] in DMF, glucopyranoside (GlcN3) was obtained in its
were in the 1-4 Hz and 6-8 Hz for the
Finally, 1-O-methyl-6-amino-6-deoxy-
anomeric form
anomerization processes
α and β anomers,
D
-
α
affording the final corresponding gold(III)-dithiocarbamato only and, as expected, no
α to β
glycoconjugates [AuIIIBr2(SSC-Inp-GlcN1)] (Au3), [AuIIIBr2(SSC- occurred.
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By reacting the zinc(II) precursors Zn4 and Zn5 with 2 eq. of
[AuICl(PPh3)] in
DMF, the corresponding gold(I)-
dithiocarbamato derivatives [AuI(SSC-Inp-GlcN2)(PPh3)] (Au6
)
and [AuI(SSC-Inp-GlcN3)(PPh3)] (Au7) were obtained (Scheme
6) and characterized by elemental analysis, IR and NMR
spectroscopy. Consistently with other triphenylphosphino-
gold(I)-dithiocarbamato complexes reported in the literature,64
those gold(I) compounds were expected to exhibit a near-
linear geometry around the metal center with the
dithiocarbamato scaffold acting as a monodentate ligand.
Although attempts to grow crystals of Au6 and Au7 proved
unsuccessful, the proposed molecular structure was confirmed
by the presence in the mid-IR spectra of two bands at ca. 1000
and 914 cm-1 assignable to the stretching vibration of the
S=C−S moiety. This is in agreement with the Bonati-Ugo
criterion, according to which a split band in the 1050-900 cm-1
spectral region with a splitting larger than 20 cm-1 indicates
monodentate bonding of the dithiocarbamato ligand.65
1
Compared with the gold(III) counterparts Au4 and Au5, the H
and 13C peaks of the glucosedithiocarbamato scaffold are
recorded at similar chemical shifts with the exception of the
atoms closer to the gold(I) core, which are more sensitive to
the different metal center and coordination mode of the
−
NCSS group. In particular, a significant downfield shift is
observed for the C2ˈ,6ˈHeq (1H: 4.9 ppm (+0.7 ppm); 13C:
51
ppm (+2 ppm)) and the NCSS (13C:
203 ppm (+16 ppm))
moieties which, together with the detection of the (N CSS)
vibration at lower energy
1485 cm-1 (-70 cm-1)), are
∼
∼
∼
ν
−
(
∼
consistent with a smaller electron-withdrawing effect upon
moving from the gold(III) to the less positively charged gold(I)
center.41
Figure 4 Comparison of the 1H ( ) and 13C{1H} (
A B) NMR spectra
in
glucopyranoside
[AuIIIBr2(SSC-Inp-GlcN3)] (Au5).
DMSO-D6
of
1-O-methyl-6-amino-6-deoxy-
α-D-
(
GlcN3), [ZnII(SSC-Inp-GlcN3)2]
(
Zn5) and
Glycoconjugation via transmetallation was achieved also in
presence of platinum(II). Reaction of the zinc(II) precursors Zn4
and Zn5 with (PPh4)[PtIICl3(NH3)] led to the formation of the
complexes [PtII(SSC-Inp-GlcN2)2]
GlcN3)2] (Pt2) (Scheme 6), although the original plan was to
synthesize the corresponding mono-dithiocarbamato
(
Pt1
)
and [PtII(SSC-Inp-
Gold(I)- and platinum(II)-dithiocarbamato glycoconjugates
The feasibility of the glycoconjugation strategy here proposed
was assessed also towards metal centers other than gold(III).
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derivatives [PtIICl(SSC-Inp-GlcN)(NH3)]. In fact, notwithstanding resonate at chemical shifts almost identical to those of their
various attempts and the exploitation of different counterparts in the zinc(II) precursor Zn5 Pt2 is undoubtedly a
,
experimental conditions, the replacement of all the chlorido different compound, as evidenced by the major upfield shift of
and amino ligands with two dithiocarbamato ligands occurred, the 1H and 13C peaks associated with the C2ˈ,6ˈHeq group.
even when a large excess (5 eq.) of the starting platinum(II) Moreover, the 13C peak at 207 ppm assigned to the
reagent was used.
dithiocarbamato carbon atom is fully consistent with those
Although no crystals of the platinum(II) glycoconjugates were reported in the literature for other bis-dithiocarbamato-
obtained, elemental analysis and spectroscopic results support platinum(II) derivatives.66a
the formation of the bis-dithiocarbamato adducts. In this Remarkably, no signals attributable to the NH3 ligand were
regard, the N
1554 cm-1 (compared with the same absorption recorded at the 15N-labeled analogues of Pt1 and Pt2 by reacting Zn4 and
1494 cm-1 for the zinc(II) precursors) are in agreement with Zn5 with the platinum(II) precursor (PPh4)[PtIICl3(15NH3)], and
−
CSS stretching vibrations observed at 1523 and observed in the 1H NMR spectra. In this regard, we synthesized
∼
data reported in the literature for analogous bis- both the IR and NMR spectra turned out to be identical to
dithiocarbamato-platinum(II) derivatives.66 Moreover, the those of the unlabeled counterparts (data not shown). In
absence in the IR spectra of the bands associated with both particular, no 15N peaks were recorded in the corresponding
the NH3 ligand (at
cm-1) and the chloride ligand (
the hypothesis of a complete exchange of ligands in favor of Notwithstanding
∼
3200 (
ν
a,s),
∼
1640 (
δ
a),
∼
1290 (
δ
s),
∼
780 (
ρ
)
[1H,15N] HSQC spectra, thus confirming that the NH3 ligand was
ν
(Pt Cl) at
−
∼
330 cm-1)67 supports replaced.
the
desired
mono-dithiocarbamato-
the dithiocarbamato ligands.
platinum(II) glycoconjugates were not obtained, the
transmetallation reaction proved successful anyway. In
perspective, this issue might be overcome by using
organophosphino (instead of amino) platinum(II) precursors as
recently reported.68
Conclusions
We have developed a relatively facile and efficient synthetic
strategy to the functionalization of metal complexes with
carbohydrates based on the initial synthesis of the zinc(II)-
dithiocarbamato glycoconjugate intermediates followed by the
transfer of the glucosedithiocarbamato ligand to other metal
centers via transmetallation. Although transmetallation of
dithiocarbamates has been known for decades, to the best of
our knowledge, its systematic application to glycoconjugation
has not been reported to date.
The main features of the proposed synthetic route are the
following.
•
•
•
It proved successful with different amino-glucose
substrates, and no protection/deprotection of the glucose
units nor chromatographic purification were required. We
are now planning to extend this procedure to more
complex amino-sugars, including oligosaccharides.
Compared with the common dithiocarbamato sodium,
potassium and ammonium salts, zinc(II)-dithiocarbamato
glycoconjugate precursors are reasonably stable over time,
can be synthesized in bulk in high yields and purity, and
stored safely for subsequent transmetallation reactions.
Transmetallation was achieved in high yields and purity for
different metal ions, such as gold(III), gold(I) and
platinum(II). We are now in the process of exploiting the
same approach with organometallic-gold(III), carbene-
gold(I) and carbonyl-manganese(I) precursors.
Figure 5 Comparison of the 1H ( ) and 13C{1H} (
A B) NMR spectra
in DMSO-D6 of [ZnII(SSC-Inp-GlcN3)2] (Zn5) and [PtII(SSC-Inp-
GlcN3)2] (Pt2
)
Given the potential biological applications of metal
glycoconjugates, in particular for the targeted metal-based
chemotherapy and diagnosis, the synthetic protocol here
optimized and proposed may be applied to a number of
different metal scaffolds, thus being of interest for scientists
As far as the NMR characterization is concerned, an illustrative
1
example is given in Figure 5. The H and 13C{1H} spectra of Pt2
are very clean and clearly indicate the presence of only one
species in solution. Although the majority of the signals
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(dec.). Anal. (%) calcd. for C22H26N4O8S4Zn (MM = 668.09 g mol-
1): C, 39.55; H, 3.92; N, 8.39; found: C, 39.31; H, 3.98; N, 8.28.
working in the field of medicinal inorganic and bioinorganic
chemistry.
FT-IR (CsI disk; 298 K): ṽmax 1817 (
oop, C=O succinimidyl), 1737 ( , C=O ester), 1496 (
1206 ( , C OSu), 1001 ( a, SCS), 562 ( s, SCS), 397 (
cm-1. H NMR (400 MHz; DMSO-D6; 298 K):
4.72 (4 H, br d,
C2ˈ,6ˈHeq), 3.52 (4 H, br t, C2ˈ,6ˈHax), 3.26-3.19 (2 H, m, C4ˈ
), 2.82
(8 H, s, CH2 succinimidyl), 2.10 (4 H, dd, C3ˈ,5ˈHeq), 1.70 (4 H, qd,
C3ˈ,5ˈHax) ppm. 13C{1H} NMR (100 MHz; DMSO-D6; 298 K):
203.3 (N SS), 170.2 ( =O succinimidyl), 169.9 ( =O ester), 49.9
C2ˈ,6ˈH2), 36.3 (C4ˈH), 27.6 (C3ˈ,5ˈH2), 25.5 (
H2 succinimidyl)
ν
ip, C=O succinimidyl), 1784
, N CSS),
a, ZnS4)
(
ν
ν
ν
−
Experimental Section
ν
−
ν
ν
ν
1
Materials and general methods (including instrumentation
used) are available in the ESI.
δ
H
Amino-sugar precursors
δ
2-Amino-2-deoxy-(α,β)-D-glucose (aka (α,β)-D-glucosamine,
GlcN1) hydrochloride was commercially available, whereas 1-
C
C
C
(
C
59
O-methyl-2-amino-2-deoxy-(
and 1-O-methyl-6-amino-6-deoxy-
GlcN3),60 were synthesized according to literature
α
,
β
)-D
-glucopyranoside
(GlcN2)
ppm.
α
-D
-glucopyranoside
[ZnII(SSC-Inp-OEt)2] (Zn1). CS2 (400 μL, 6.63 mmol) was added
dropwise under stirring to a water/ethanol (7:3, 10 mL)
solution of ethyl isonipecotate (1.03 g, 6.53 mmol) at 0°C. The
mixture was stirred at 0°C for 3 h (pH turned from 12 to 6), and
then added to an aqueous solution (3 mL) of ZnCl2 (220.0 mg,
1.63 mmol), leading to the sudden precipitation of a white
solid. The precipitate was centrifuged and the bulk of
supernatant discarded. The residue was subsequently washed
(
procedures. Detailed syntheses and characterizations are
reported in the ESI.
Zinc(II)-dithiocarbamato intermediates
Na2[ZnII(SSC-Inp-O)2]∙2H2O (Zn0a). This zinc(II) intermediate was
synthesized according to a modified literature procedure.58 NaOH
(620.0 mg, 15.50 mmol) was dissolved in methanol (7 mL) and
added under stirring to a methanol solution (10 mL) of isonipecotic
acid (1.00 g, 7.74 mmol). The mixture was cooled down to 0°C,
treated dropwise with CS2 (480 μL, 7.94 mmol), and stirred for 6
h. The resulting solution was then added dropwise under
stirring to a methanol solution (7 mL) of [Zn(OAc)2]∙2H2O
(850.0 mg, 3.87 mmol), leading to the sudden precipitation of
a white solid. The precipitate was centrifuged and the bulk of
supernatant discarded. The residue was subsequently washed
with water (2×10 mL), acetone (2×10 mL) and diethyl ether
(2 10 mL), and then dried under vacuum over P2O5, yielding
×
the title compound as a white solid (620.1 mg, 72%). Small
colorless plate-shaped crystals suitable for X-ray
crystallography were obtained upon slow evaporation of an
acetonitrile/ethanol solution of the compound. M.p. 200-
202°C. Anal. (%) calcd. for C18H28N2O4S4Zn (MM = 530.05 g mol-
1): C, 40.79; H, 5.32; N, 5.29; found: C, 40.57; H, 5.39; N, 5.10.
with methanol (3×20 mL) and then dried under vacuum over
FT-IR (CsI disk; 298 K): ṽmax 1733 (
1176 ( , C OEt), 1042 ( , O Et), 1007 (
398 (
a, ZnS4) cm-1. 1H NMR (400 MHz; DMSO-D6; 298 K):
4.72 (4 H, dt, C2ˈ,6ˈHeq), 4.08 (4 H, q, OCH2), 3.39 (4 H, td,
C2ˈ,6ˈHax), 2.72-2.60 (2 H, m, C4ˈ ), 1.95 (4 H, dd, C3ˈ,5ˈHeq), 1.57
(4 H, qd, C3ˈ,5ˈHax), 1.19 (6 H, t, CH3) ppm. 13C{1H} NMR (100
MHz; DMSO-D6; 298 K): 202.6 (N SS), 173.6 ( =O), 60.2
(O H3)
H2), 50.4 (C2ˈ,6ˈH2), 38.9 (C4ˈH), 27.8 (C3ˈ,5ˈH2), 14.1 (
ppm.
ν
, C=O), 1494 (
ν
, N
−CSS),
P2O5, yielding the title compound as a white solid (1.47 g,
68%). M.p. 295-297°C (dec.). Anal. (%) calcd. for
C14H22N2Na2O6S4Zn (MM = 553.94 g mol-1): C, 30.36; H, 4.00; N,
5.06; found: C, 30.48; H, 4.08; N, 5.04. FT-IR (CsI disk; 298 K):
ν
ν
−
ν
−
νa, SCS), 568 (
νs, SCS),
δ
H
ṽmax 1555 (
a, SCS), 566 (
D2O; 298 K):
C2ˈ,6ˈHax), 2.46 (2 H, tt, C4ˈ
qd, C3ˈ,5ˈHax) ppm. 13C{1H} NMR (100 MHz; D2O; 298 K):
(N SS), 183.1 (
OO-), 51.8 (C2ˈ,6ˈH2), 42.8 (C4ˈH), 28.8 (C3ˈ,5ˈH2)
ppm.
ν
a, COO-), 1487 (
s, SCS), 397 (
4.93 (4 H, br dt, C2ˈ,6ˈHeq), 3.31 (4 H, br td,
), 1.95 (4 H, dd, C3ˈ,5ˈHeq), 1.66 (4 H,
201.6
ν
ν
, N
−CSS), 1409 (ν
s, COO-), 1002
1
(
ν
ν
δ
a, ZnS4) cm-1. H NMR (400 MHz;
δ
C
C
C
C
H
δ
[ZnII(SSC-Inp-NH2)2] (Zn2). Method A: NaOH (310.0 mg, 7.80 mmol)
was dissolved in methanol (10 mL) and added under stirring to a
methanol solution (10 mL) of isonipecotamide (1.00 g, 7.80 mmol).
The mixture was cooled down to 0°C, treated dropwise with CS2
(470 μL, 7.80 mmol), stirred for 3 h (pH turned from 12 to 8),
treated with further CS2 (470 μL, 7.80 mmol), and stored at 4°C
for 16 h. The mixture was then added to an aqueous solution
(2 mL) of [Zn(OAc)2]∙2H2O (860.0 mg, 3.90 mmol) at room
temperature, leading to the sudden precipitation of a white
solid. The precipitate was centrifuged and the bulk of
supernatant discarded. The residue was subsequently washed
C
C
[ZnII(SSC-Inp-OSu)2] (Zn0b). This zinc(II) intermediate was
synthesized according to
literature procedure.52 N,N,Nˈ,Nˈ-
a
tetramethyl-O-(N-succinimidyl)uronium tetrafluoroborate (TSTU,
3.07 g, 10.2 mmol) was added under stirring to an anhydrous DMF
suspension (12 mL) of Zn0a (2.51 g, 4.53 mmol) and N,N-
diisopropylethylamine (DIPEA, 160 μL, 0.92 mmol). The mixture was
stirred at room temperature under inert atmosphere (N2) for 16 h
and then treated with a 1:1 water/ethanol solution (1.2 L),
affording a white solid. The precipitate was filtered off,
with water (2×15 mL) and then dried under vacuum over P2O5,
washed with ethanol (3×20 mL) and diethyl ether (3×20 mL),
and then dried under vacuum over P2O5, yielding the title
yielding the title compound as a white solid (1.77 g, 96%).
Method B: An aqueous solution (18 mL) of Na(SSC-Inp-
NH2)∙CH3OH (900.0 mg, 3.48 mmol; see ESI for details on
compound as a white solid (2.81 g, 93%). M.p. 220-222°C
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synthesis and characterization) was added under stirring to an
aqueous solution (2 mL) of [Zn(OAc)2]∙2H2O (380.0 mg, 1.73
mmol) at room temperature, leading to the sudden
precipitation of a white solid. The precipitate was centrifuged
and the bulk of supernatant discarded. The residue was
the presence of both α and β anomers could be observed. Solution
α:β anomers ratio ≈ 4:1 (based on the 1H NMR spectrum).
[ZnII(SSC-Inp-GlcN2)2] (Zn4). A mixture of 1-O-methyl-2-amino-2-
deoxy-(α,β)-D-glucopyranoside (GlcN2) (266.1 mg, 1.05 mmol) and
N,N-diisopropylethylamine (DIPEA, 76 ꢀL, 0.44 mmol) in anhydrous
DMF (2 mL) was added under stirring to a suspension of Zn0b
(292.8 mg, 0.44 mmol) in anhydrous DMF (2 mL). The mixture was
stirred at room temperature under inert atmosphere (N2) for 16 h
and treated with methanol (30 mL), leading to the formation of a
white precipitate that was filtered off and discarded. The resulting
clear pale yellow solution was allowed to slowly concentrate under
subsequently washed with water (2×15 mL) and then dried
under vacuum over P2O5, yielding the title compound as a
white solid (810.0 mg, 99%).
M.p. 293-294°C (dec.). Anal. (%) calcd. for C14H22N4O2S4Zn (MM
= 471.98 g mol-1): C, 35.63; H, 4.70; N, 11.87; found: C, 35.74;
H, 4.89; N, 11.76. FT-IR (CsI disk; 298 K): ṽmax 3439/3208 (νa,s
NH2), 1667 ( , C=O (amide I)), 1649 ( ip, CNH2 (amide II)), 1492
, N CSS), 1007 ( a, SCS), 561 ( s, SCS), 392 (
NMR (400 MHz; DMSO-D6; 298 K):
,
ν
δ
(
ν
−
ν
ν
ν
a, ZnS4) cm-1. 1H the fume hood at room temperature for two days. The resulting
white solid was resuspended in methanol (20 mL), filtered off,
δ
7.36 (2 H, s, NHcis), 6.87 (2
H, s, NHtrans), 4.82 (4 H, br d, C2ˈ,6ˈHeq), 3.26 (4 H, td, C2ˈ,6ˈHax), washed with methanol (3×20 mL), and then dried under vacuum
2.40 (2 H, tt, C4ˈ
H
), 1.82 (4 H, dd, C3ˈ,5ˈHeq), 1.54 (4 H, qd, over P2O5, yielding the title compound as a white solid (464.6 mg,
C3ˈ,5ˈHax) ppm. 13C{1H} NMR (100 MHz; DMSO-D6; 298 K):
202.3 (N SS), 175.6 (
=O), 50.7 (C2ˈ,6ˈH2), 40.1 (C4ˈH), 28.4
C3ˈ,5ˈH2) ppm.
δ
35%). M.p. 268-272°C (dec.). Anal. (%) calcd. for C28H46N4O12S4Zn
(MM = 824.31 g mol-1): C, 40.80; H, 5.63; N, 6.80; found: C, 40.65; H,
5.74; N, 6.81. FT-IR (CsI disk; 298 K): ṽmax 3319br (ν, OH + NH
overlapped), 1645 (ν, C=O (amide I)), 1557 (δip, CNH (amide II)),
1494 (ν, N−CSS), 1062br/1040br (ν, C−OH + C1−O−CH3 overlapped),
1007 (νa, SCS), 576 (νs, SCS), 366 (νa, ZnS4) cm-1. 1H NMR (400 MHz;
C
C
(
[ZnII(SSC-Inp-GlcN1)2] (Zn3).
A mixture of (α,β)-D-glucosamine
(GlcN1) hydrochloride (392.0 mg, 1.82 mmol) and N,N-
diisopropylethylamine (DIPEA, 925 ꢀL, 5.31 mmol) in anhydrous
DMF (3 mL) was added under stirring to a suspension of Zn0b
(473.3 mg, 0.71 mmol) in anhydrous DMF (2 mL). The mixture was
stirred at room temperature under inert atmosphere (N2) for 16 h
and then treated with methanol (60 mL), leading to the sudden
precipitation of a white solid. The precipitate was filtered off,
washed with methanol (3×20 mL), and then dried under vacuum
over P2O5, yielding the title compound as a white solid (341.6 mg,
61%). M.p. 200-203°C (dec.). Anal. (%) calcd. for C26H42N4O12S4Zn
(MM = 796.26 g mol-1): C, 39.22; H, 5.32; N, 7.04; found: C, 39.18; H,
5.19; N, 6.91. FT-IR (CsI disk; 298 K): ṽmax 3293br (ν, OH + NH
overlapped), 1638 (ν, C=O (amide I)), 1547 (δip, CNH (amide II)),
1487 (ν, N−CSS), 1071br/1060br (ν, C−OH), 1005 (νa, SCS), 570 (νs,
DMSO-D6; 298 K): δ
7.80 (2 H, d, NH), 5.00 (2 H, d, C4OH), 4.82 (4 H,
br d, C2ˈ,6ˈHeq), 4.73 (2 H, d, C3OH), 4.56-4.52 (4 H, m, C6OH + C1H
overlapped), 3.67-3.42 (8 H, m, C2H + C3H + C6H2 overlapped), 3.33-
3.24 (6 H, m, C5H + C2ˈ,6ˈHax overlapped), 3.24 (6 H, s, OCH3), 3.15-
3.09 (2 H, m, C4H), 2.59-2.52 (2 H, m, C4ˈH), 1.81-1.76 (4 H, br m,
C3ˈ,5ˈHeq), 1.57 (4 H, br qd, C3ˈ,5ˈHax) ppm. The 1H NMR signals refer to
the α anomer. Signals related to the β anomer were hardly
detectable, and only a very few were observed and could be
undoubtedly assigned (such as
= 4.19 (3J1,2 = 8.4 Hz), (OCH3) = 3.58 ppm). 13C{1H} NMR (100 MHz;
DMSO-D6; 298 K):
202.2 (NCSS), 173.9 (C=O), 97.9 (C1H), 72.8
δ(NH) = 7.68, δ δ
(C3OH) = 4.91, (C1H)
δ
δ
(C5H), 70.8 (C3H), 70.7 (C4H), 60.9 (C6H2), 54.5 (OCH3), 53.8 (C2H),
50.8 (C2ˈ,6ˈH2), 40.0 (C4ˈH), 28.5 (C3ˈ,5ˈH2) ppm. No 13C signals
assignable to the β anomer were detected. Solution α:β anomers
ratio ≈ 25:1 (based on the 1H NMR spectrum).
SCS), 373 (νa, ZnS4) cm-1. 1H NMR (400 MHz; DMSO-D6; 298 K):
δ
7.70 (0.5 H, d, NH β), 7.67 (2 H, d, NH α), 6.49 (0.5 H, d, C1OH β),
6.41 (2 H, d, C1OH α), 4.94-4.90 (4 H, m, C3OH + C1H α overlapped),
4.85-4.78 (5 H, br m, C2ˈ,6ˈHeq α and β overlapped), 4.61 (2 H, d, [ZnII(SSC-Inp-GlcN3)2] (Zn5). A mixture of 1-O-methyl-6-amino-6-
C4OH α), 4.53 (0.5 H, dd, C6OH β), 4.45-4.42 (2.5 H, br m, C6OH α + deoxy-α-D-glucopyranoside (GlcN3, 760.0 mg, 3.93 mmol) and N,N-
C1H β overlapped), 3.69-3.39 (11.5 H , m, C2H α + C4H α and β + C5H
diisopropylethylamine (DIPEA, 1.50 mL, 8.64 mmol) in anhydrous
α + C6H2 α and β overlapped), 3.31-3.22 (6 H, m, C2ˈ,6ˈHax α and β +
DMF (4 mL) was added under stirring to a suspension of Zn0b (1.05
C2H β + C3H β overlapped), 3.18-3.02 (2.5 H, m, C3H α + C5H β
g, 1.57 mmol) in anhydrous DMF (4 mL). The mixture was stirred at
overlapped), 2.57-2.52 (2.5 H, m, C4ˈH α and β overlapped), 1.81-
room temperature under inert atmosphere (N2) for 16 h and then
1.75 (5 H, m, C3ˈ,5ˈHeq α and β overlapped), 1.62-1.56 (5 H, br qd,
treated with ethanol (80 mL), leading to the sudden precipitation
C3ˈ,5ˈHax α and β overlapped) ppm. C3OH β and C4OH β could not be
of a white solid. The precipitate was filtered off, washed with
methanol (3×15 mL), and then dried under vacuum over P2O5,
yielding the title compound as a white solid (980.0 mg, 76%). M.p.
245-248°C (dec.). Anal. (%) calcd. for C28H46N4O12S4Zn (MM = 824.31
g mol-1): C, 40.80; H, 5.63; N, 6.80; found: C, 40.91; H, 5.83; N, 6.76.
FT-IR (CsI disk; 298 K): ṽmax 3392br (ν, OH + NH overlapped), 1637 (ν,
C=O (amide I)), 1543 (δip, CNH (amide II)), 1494 (ν, N−CSS), 1050br
(ν, C−OH + C1−O−CH3 overlapped), 1010 (νa, SCS), 564 (νs, SCS), 366
undoubtedly assigned: those peaks are probably overlapped with
other peaks in the 4.92-4.42 ppm range. 13C{1H} NMR (100 MHz;
DMSO-D6; 298 K):
δ
202.2 (NCSS), 173.8 (C=O), 95.4 (C1H β), 90.5
(C1H α), 76.9 (C5H β), 74.2 (C3H β), 72.1 (C5H α), 71.1 (C3H α), 70.9
(C4H β), 70.4 (C4H α), 61.2 (C6H2 β), 61.1 (C6H2 α), 57.1 (C2H β), 54.3
(C2H α), 50.8 (C2ˈ,6ˈH2), 40.1 (C4ˈH), 28.5 (C3ˈ,5ˈH2) ppm. No
differentiation of the 13C signals of the isonipecotic moiety due to
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ARTICLE
Dalton Transactions
(νa, ZnS4) cm-1. 1H NMR (400 MHz; DMSO-D6; 298 K):
δ
7.97 (2 H, dd, ṽmax 3408/3176 (
ν
a,s, NH2), 1660 (
CNH2 (amide II)), 1565 ( , N CSS), 1007 (
411 ( a, SAuS), 397 ( s, SAuS), 232 (
BrAuBr) cm-1. 1H NMR (400 MHz; DMSO-D6; 298 K):
s, NHcis), 6.97 (2 H, s, NHtrans), 4.11 (2 H, dt, C2ˈ,6ˈHeq), 3.57 (2 H,
td, C2ˈ,6ˈHax), 2.62 (1 H, tt, C4ˈ ), 1.97 (2 H, dd, C3ˈ,5ˈHeq), 1.62 (2
H, qd, C3ˈ,5ˈHax) ppm. 13C{1H} NMR (100 MHz; DMSO-D6; 298 K):
186.9 (N SS), 174.5 (
=O), 48.4 (C2ˈ,6ˈH2), 40.3 (C4ˈH), 27.5
C3ˈ,5ˈH2) ppm.
ν
, C=O (amide I)), 1620 (δip
a, SCS), 534 ( s, SCS),
a, BrAuBr), 227 (νs
7.40 (2 H,
,
NH), 4.97 (2 H, d, C4OH), 4.83 (4 H, br m, C2ˈ,6ˈHeq), 4.82 (2 H, d,
ν
ν
−
ν
ν
ν
3
C3OH), 4.75 (2 H, d, C2OH), 4.51 (2 H, d, C1H, J1,2 = 3.6 Hz), 3.58-
ν
,
3.52 (2 H, m, C6H'), 3.40-3.35 (4 H, m, C3H + C5H overlapped), 3.24
(6 H, s, OCH3), 3.28-3.19 (6 H, m, C2H + C2ˈ,6ˈHax overlapped), 3.08-
2.98 (2 H, m, C6H''), 2.92-2.88 (2 H, m, C4H), 2.57-2.53 (2 H, m, C4ˈH),
1.78-1.75 (4 H, m, C3ˈ,5ˈHeq), 1.57 (4 H, br qd, C3ˈ,5ˈHax) ppm. 13C{1H}
δ
H
NMR (100 MHz; DMSO-D6; 298 K): δ 202.2 (NCSS), 173.8 (C=O), 99.6
δ
C
C
(C1H), 73.0 (C3H), 72.1 (C4H), 72.0 (C2H), 70.3 (C5H), 54.3 (OCH3),
50.7 (C2ˈ,6ˈH2), 39.9 (C4ˈH), 39.8 (C6H2), 28.4 (C3ˈ,5ˈH2) ppm.
(
[AuIIIBr2(SSC-Inp-GlcN1)] (Au3). A DMF solution (2 mL) of Zn3 (74.3
mg, 0.09 mmol) was added dropwise under stirring to a DMF
solution (2 mL) of K[AuBr4]∙2H2O (110.5 mg, 0.19 mmol) at room
temperature. The mixture was stirred for 3 h, after which the color
of the solution turned from dark red to orange. Addition of diethyl
ether (40 mL) resulted in the formation of an orange precipitate.
The precipitate was centrifuged and the bulk of supernatant
discarded. The residue was subsequently washed with methanol
(3×10 mL) and then dried under vacuum over P2O5, yielding the title
compound as an orange solid (100.9 mg, 75%). M.p. 210-211°C
(dec.). Anal. (%) calcd. for C13H21AuBr2N2O6S2 (MM = 722.21 g mol-
1): C, 21.62; H, 2.93; N, 3.88; found: C, 21.78; H, 3.03; N, 3.78. FT-IR
(CsI disk; 298 K): ṽmax 3306br (ν, OH + NH overlapped), 1636 (ν, C=O
(amide I)), 1561 (ν, N−CSS + δip, CNH (amide II) overlapped), 1060br
Gold(III)-dithiocarbamato complexes
[AuIIIBr2(SSC-Inp-OEt)] (Au1). A DMF solution (2 mL) of Zn1 (76.5
mg, 0.15 mmol) was added dropwise under stirring to a DMF
solution (2 mL) of K[AuBr4]∙2H2O (170.5 mg, 0.30 mmol) at
room temperature. The mixture was stirred for 3 h, after
which the color of the solution turned from dark red to
orange. Addition of a diethyl ether/n-hexane 2:1 solution (60
mL) resulted in the formation of a light orange precipitate. The
precipitate was centrifuged and the bulk of supernatant
discarded. The residue was subsequently washed with ethanol
(15 mL) and a water/ethanol 1:1 solution (2×15 mL), and then
dried under vacuum over P2O5, yielding the title compound as
an orange solid (132.2 mg, 78%). Orange shiny plate-shaped
crystals suitable for X-ray crystallography were obtained upon
(ν, C−OH), 1008 (νa, SCS), 575 (νs, SCS), 412 (
a, BrAuBr), 227 (
s, BrAuBr) cm-1. 1H NMR (400
MHz; DMSO-D6; 298 K):
νa, SAuS), 392 (νs,
slow evaporation of an acetone solution of the compound. SAuS), 244 (
ν
ν
M.p. 243-246°C (dec.). Anal. (%) calcd. for C9H14AuBr2NO2S2
(MM = 589.11 g mol-1): C, 18.35; H, 2.40; N, 2.38; found: C,
δ
7.75 (0.4 H, d, NH β), 7.73 (1 H, d, NH α),
6.45 (1.4 H, br s, C1OH α and β overlapped), 4.91 (1 H, d, C1H α, 3J1,2
= 3.1 Hz), 4.45 (0.4 H, d, C1H β, J1,2 = 7.8 Hz), 4.12 (2.8 H, br dt,
3
18.27; H, 2.39; N, 2.25. FT-IR (CsI disk; 298 K): ṽmax 1729 (
C=O), 1571 ( , N CSS), 1183 ( , C OEt), 1040 ( , O Et), 1002
a, SCS), 536 ( s, SCS), 413 ( a, SAuS), 398 ( s, SAuS), 249 (νa
BrAuBr), 228 (
s, BrAuBr) cm-1. H NMR (400 MHz; DMSO-D6;
298 K):
4.09 (2 H, q, OCH2), 4.07-4.05 (2 H, m, C2ˈ,6ˈHeq), 3.61
(2 H, td, C2ˈ,6ˈHax), 2.90 (1 H, tt, C4ˈ ), 2.08 (2 H, dd, C3ˈ,5ˈHeq),
1.75 (2 H, qd, C3ˈ,5ˈHax), 1.19 (3 H, t, CH3) ppm. 13C{1H} NMR
(100 MHz; DMSO-D6; 298 K): 187.9 (N SS), 173.2 ( =O), 60.9
(O H3)
H2), 48.6 (C2ˈ,6ˈH2), 39.0 (C4ˈH), 27.3 (C3ˈ,5ˈH2), 14.6 (
ppm.
ν,
C2ˈ,6ˈHeq α and β overlapped), ∼4.0 (4.2 H, br s, C3OH + C4OH + C6OH
α and β overlapped), 3.69-3.39 (9 H , m, C2H α + C4H α and β + C5H
α + C6H2 α and β, C2ˈ,6ˈHax α and β overlapped), 3.37-3.23 (0.8 H, m,
C2H β + C3H β overlapped), 3.11-3.04 (1.4 H, m, C3H α + C5H β
overlapped), 2.75 (1 H, tt, C4ˈH α), 2.63 (0.4 H, tt, C4ˈH β), 1.98-1.91
(2.8 H, br m, C3ˈ,5ˈHeq α and β overlapped), 1.75-1.67 (2.8 H, br m,
C3ˈ,5ˈHax α and β overlapped) ppm. 13C{1H} NMR (100 MHz; DMSO-
ν
−
ν
−
ν
−
(
ν
ν
ν
ν
ν
,
1
δ
H
δ
C
C
C
C
D6; 298 K):
δ 186.9 (NCSS α; β not detected), 172.8 (C=O α), 172.7
(C=O β), 95.3 (C1H β), 90.5 (C1H α), 76.9 (C5H β), 74.2 (C3H β), 72.1
(C5H α), 71.1 (C3H α), 70.8 (C4H β), 70.4 (C4H α), 61.2 (C6H2 β), 61.1
(C6H2 α), 57.2 (C2H β), 54.3 (C2H α), 48.4 (C2ˈ,6ˈH2 α), 48.3 (C2ˈ,6ˈH2 β),
40.5 (C4ˈH β), 40.1 (C4ˈH α), 27.8 (C3ˈ,5ˈH2 α), 27.3 (C3ˈ,5ˈH2 β) ppm.
Solution α:β anomers ratio ≈ 2.5:1 (based on the 1H NMR
spectrum).
[AuIIIBr2(SSC-Inp-NH2)] (Au2). A suspension of Zn2 (42.0 mg, 0.09
mmol) in DMF (8 mL) was added dropwise under stirring to a
DMF solution (2 mL) of K[AuBr4]∙2H2O (105.4 mg, 0.18 mmol)
at room temperature. The mixture was stirred for 1.5 h, after
which the suspension dissolved completely and the color of
the solution turned from dark red to orange. Addition of
diethyl ether (100 mL) led to the precipitation of an orange
residue. The precipitate was centrifuged and the bulk of
supernatant discarded. The residue was subsequently washed
[AuIIIBr2(SSC-Inp-GlcN2)] (Au4). A DMF solution (2 mL) of Zn4 (88.6
mg, 0.11 mmol) was added dropwise under stirring to a DMF
solution (3 mL) of K[AuBr4]∙2H2O (128.6 mg, 0.22 mmol) at room
temperature. The mixture was stirred for 3 h, after which the color
of the solution turned from dark red to orange. Addition of diethyl
ether (50 mL) resulted in the formation of an orange precipitate.
The precipitate was centrifuged and the bulk of supernatant
discarded. The residue was subsequently washed with methanol
(3×10 mL) and then dried under vacuum over P2O5, yielding the title
with methanol (3×15 mL) and then dried under vacuum over
P2O5, yielding the title compound as an orange solid (69.3 mg,
70%). M.p. 268-272°C (dec.). Anal. (%) calcd. for
C7H11AuBr2N2OS2 (MM = 560.07 g mol-1): C, 15.01; H, 1.98; N,
5.00; found: C, 15.06; H, 2.09; N, 4.96. FT-IR (CsI disk; 298 K):
12 | Dalton Trans., 20xx, xx, x-x
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compound as an orange solid (129.1 mg, 81%). M.p. 198-202°C
(dec.). Anal. (%) calcd. for C14H23AuBr2N2O6S2 (MM = 736.24 g mol-
1): C, 22.84; H, 3.15; N, 3.81; found: C, 22.85; H, 2.98; N, 3.75. FT-IR
(CsI disk; 298 K): ṽmax 3400br/3296br (ν, OH + NH overlapped), 1649 (dec.). Anal. (%) calcd. for C32H38AuN2O6PS2 (MM = 838.72 g mol-1):
triturated with a 1:1 diethyl ether/dichloromethane mixture (3×10
mL), and then dried under vacuum over P2O5, yielding the title
compound as a light yellow solid (80.2 mg, 60%). M.p. 188-190°C
C, 45.83; H, 4.57; N, 3.34; found: C, 45.92; H, 4.63; N, 3.29. FT-IR (CsI
(ν, C=O (amide I)), 1561 (ν, N−CSS + δip, CNH (amide II) overlapped),
1059br/1040br (ν, C−OH + C1−O−CH3 overlapped), 1007 (νa, SCS),
disk; 298 K): ṽmax 3424br (ν, OH + NH overlapped), 1651 (ν, C=O
(amide I)), 1545 (δip, CNH (amide II)), 1490 (ν, N−CSS), 1100 (νq vib
,
577 (νs, SCS), 410 (
ν
a, SAuS), 393 (
s, BrAuBr) cm-1. 1H NMR (400 MHz; DMSO-D6; 298 K):
ν
s, SAuS), 246 (
ν
a, BrAuBr),
P−Ph3), 1056br (ν, C−OH + C1−O−CH3 overlapped), 1001/914 (ν,
220 (
ν
δ
7.86
(1 H, d, NH), 4.97 (3 H, br s, C3OH + C4OH + C6OH overlapped), 4.52 S=C−S), 710/694 (νr vib, P−Ph3), 578 (ν, C−S), 539/509/500 (δy
,
vib
(1 H, d, C1H, 3J1,2 = 3.5 Hz), 4.12 (2 H, br dt, C2ˈ,6ˈHeq), 3.68-3.27 (7 H,
m, C2ˈ,6ˈHax + C2H + C3H + C5H + C6H2 overlapped), 3.24 (3 H, s,
OCH3), 3.12 (1 H, dd, C4H), 2.75 (1 H, tt, C4ˈH), 1.98-1.91 (2 H, m,
C3ˈ,5ˈHeq), 1.76-1.66 (2 H, m, C3ˈ,5ˈHax) ppm. 13C{1H} NMR (100 MHz;
P−Ph3), 427 (νt vib, P−Ph3), 380 (
ν
, Au x vib, P
−
S), 273/240 (
δ
−Ph3 +
1
ν, Au
−
P) cm-1. H NMR (400 MHz; DMSO-D6; 298 K):
δ 7.80 (1 H, d,
NH), 7.59-7.50 (15 H, m, CH Ph), 5.01 (1 H, d, C4OH), 4.90 (2 H, br dt,
C2ˈ,6ˈHeq), 4.71 (1 H, d, C3OH), 4.55 (1 H, d, C6OH), 4.53 (1 H, d, C1H,
3J1,2 = 3.1 Hz), 3.68-3.61 (2 H, m, C2H + C6H' overlapped), 3.49-3.42
(2 H, m, C3H + C6H'' overlapped), 3.33-3.26 (3 H, m, C2ˈ,6ˈHax + C5H
overlapped), 3.24 (3 H, s, OCH3), 3.15-3.09 (1 H, m, C4H), 2.59-2.53
(1 H, br tt, C4ˈH), 1.83-1.75 (2 H, m, C3ˈ,5ˈHeq), 1.65-1.55 (2 H, m,
DMSO-D6; 298 K):
δ
186.9 (NCSS), 172.9 (C=O), 97.8 (C1H), 72.8
(C5H), 70.8 (C3H), 70.7 (C4H), 60.8 (C6H2), 54.4 (OCH3), 53.7 (C2H),
48.4 (C2ˈ,6ˈH2), 40.3 (C4ˈH), 27.7 (C3ˈ,5ˈH2) ppm. No NMR signals
assignable to the β anomer were detected.
C3ˈ,5ˈHax) ppm. 13C{1H} NMR (100 MHz; DMSO-D6; 298 K):
δ 202.2
[AuIIIBr2(SSC-Inp-GlcN3)] (Au5). A DMF solution (3 mL) of Zn5
(101.7 mg, 0.12 mmol) was added dropwise under stirring to a DMF
solution (3 mL) of K[AuBr4]∙2H2O (148.8 mg, 0.25 mmol) at room
temperature. The mixture was stirred for 2 h, after which the color
of the solution turned from dark red to orange. Addition of diethyl
ether (60 mL) resulted in the formation of an orange precipitate.
The precipitate was centrifuged and the bulk of supernatant
discarded. The residue was subsequently washed with methanol
(3×10 mL) and then dried under vacuum over P2O5, yielding the title
compound as an orange solid (161.2 mg, 87%). M.p. 217-220°C
(dec.). Anal. (%) calcd. for C14H23AuBr2N2O6S2 (MM = 736.24 g mol-
1): C, 22.84; H, 3.15; N, 3.81; found: C, 22.95; H, 3.07; N, 3.78. FT-IR
(CsI disk; 298 K): ṽmax 3400br (ν, OH + NH overlapped), 1650 (ν, C=O
(amide I)), 1555 (ν, N−CSS + δip, CNH (amide II) overlapped), 1050br
(ν, C−OH + C1−O−CH3 overlapped), 1011 (νa, SCS), 570 (νs, SCS),
2
(NCSS), 173.9 (C=O), 133.5 (d, o-CH, JC,P = 14.3 Hz), 131.9 (d, p-CH,
1
4JC,P = 2.0 Hz), 130.1 (d, CP, JC,P = not detectable due to
overlapping), 129.5 (d, m-CH, 3JC,P = 11.3 Hz), 97.9 (C1H), 72.8 (C5H),
70.8 (C3H), 70.7 (C4H), 60.8 (C6H2), 54.5 (OCH3), 53.8 (C2H), 50.8
(C2ˈ,6ˈH2), 40.3 (C4ˈH), 28.4 (C3ˈ,5ˈH2) ppm. 31P{1H} NMR (162 MHz;
DMSO-D6; 298 K): δ 36.5 (AuPPh3) ppm.
[AuI(SSC-Inp-GlcN3)(PPh3)] (Au7). A DMF solution (2 mL) of
Zn5 (67.0 mg, 0.08 mmol) was added dropwise under stirring
to a DMF solution (2 mL) of [AuCl(PPh3)] (80.4 mg, 0.16 mmol)
at room temperature, and the mixture was stirred for 1 h.
Upon addition of diethyl ether (40 mL), the solution turned
cloudy and a white solid residue formed. The precipitate was
centrifuged and the bulk of supernatant discarded. The sticky
residue was subsequently triturated with
a 1:1 diethyl
ether/dichloromethane mixture (3×10 mL), and then dried
398br
(
νa,s, SAuS), 254 (
νa, BrAuBr), 227 (
ν
s, BrAuBr) cm-1. 1H
under vacuum over P2O5, yielding the title compound as a light
yellow solid (95.2 mg, 70%). M.p. 162-166°C (dec.). Anal. (%)
calcd. for C32H38AuN2O6PS2 (MM = 838.72 g mol-1): C, 45.83; H,
4.57; N, 3.34; found: C, 45.96; H, 4.56; N, 3.39. FT-IR (CsI disk;
NMR (400 MHz; DMSO-D6; 298 K):
δ
7.99 (1 H, dd, NH), 4.51 (1 H, d,
3
C1H, J1,2 = 3.6 Hz), 4.13 (2 H, br d, C2ˈ,6ˈHeq), 3.60 (3 H, br s, C2OH +
C3OH + C4OH overlapped), 3.59-3.53 (3 H, m, C6H' + C2ˈ,6ˈHax
overlapped), 3.37-3.30 (2 H, m, C3H + C5H overlapped), 3.24 (3 H, s,
OCH3), 3.21-3.17 (1 H, m, C2H), 3.05-2.94 (1 H, m, C6H''), 2.90 (1 H,
dd, C4H), 2.71 (1 H, br tt, C4ˈH), 1.93 (2 H, td, C3ˈ,5ˈHeq), 1.71 (2 H, qd,
298 K): ṽmax 3429br
(amide I)), 1544 ( ip, CNH (amide II)), 1483 (
vib, P Ph3), 1051br , C CH3 overlapped), 1000/914
OH + C1
, S=C S), 711/694 ( r vib, P Ph3), 577 ( , C S), 539/510/500
y vib, P Ph3), 437 ( t vib, P Ph3), 397 ( , Au S), 262/241 (δx vib
Ph3 + , Au
P) cm-1. H NMR (400 MHz; DMSO-D6; 298 K):
7.98 (1 H, dd, N ), 7.60-7.52 (15 H, m, C
C4O ), 4.89 (2 H, br d, C2ˈ,6ˈHeq), 4.82 (1 H, d, C3O
d, C2O ), 4.51 (1 H, d, C1 , 3J1,2 = 3.7 Hz), 3.55 (1 H, ddd, C6
3.38-3.33 (2 H, m, C3 + C5
overlapped), 3.24 (3 H, s, OCH3),
3.24-3.17 (3 H, m, C2 + C2ˈ,6ˈHax overlapped), 3.01 (1 H, td,
C6 ''), 2.93-2.87 (1 H, m, C4 ), 2.55 (1 H, br tt, C4ˈ
), 1.79-1.75
(2 H, m, C3ˈ,5ˈHeq), 1.65-1.56 (2 H, m, C3ˈ,5ˈHax) ppm. 13C{1H}
NMR (100 MHz; DMSO-D6; 298 K): 203.6 (N SS), 173.9 ( =O),
H, JC,P = 15.7 Hz), 131.9 (d, p- H, JC,P = 2.8 Hz),
(
ν, OH + NH overlapped), 1654 (
ν, C=O
δ
ν
, N CSS), 1101 (νq
−
−
(ν
−
−O−
C3ˈ,5ˈHax) ppm. 13C{1H} NMR (100 MHz; DMSO-D6; 298 K):
δ 187.0
(
(
ν
δ
−
−
−
ν
−
ν
−
(NCSS), 172.7 (C=O), 99.6 (C1H), 73.0 (C3H), 72.1 (C4H), 71.9 (C2H),
70.3 (C5H), 54.4 (OCH3), 48.4 (C2ˈ,6ˈH2), 40.5 (C4ˈH), 40.1 (C6H2), 27.7
(C3ˈ,5ˈH2) ppm.
ν
−
ν
−
,
1
P
ν
−
δ
H
H
Ph), 4.98 (1 H, d,
), 4.76 (1 H,
'),
H
H
H
H
H
Gold(I)-dithiocarbamato complexes
H
H
[AuI(SSC-Inp-GlcN2)(PPh3)] (Au6). A DMF solution (2 mL) of Zn4
(65.0 mg, 0.08 mmol) was added dropwise under stirring to a DMF
solution (2 mL) of [AuCl(PPh3)] (78.0 mg, 0.16 mmol) at room
temperature, and the mixture was stirred for 1 h. Upon addition of
diethyl ether (40 mL), the solution turned cloudy and a white solid
residue formed. The precipitate was centrifuged and the bulk of
supernatant discarded. The sticky residue was subsequently
H
H
H
H
δ
C
C
2
4
133.7 (d, o-
C
C
1
129.8 (d, CP, JC,P = not detectable due to overlapping), 129.5
3
(d, m-
C
H, JC,P = 11.9 Hz), 99.6 (C1H), 73.0 (C3H), 72.1 (C4H),
This journal is © The Royal Society of Chemistry 20xx
Dalton Trans., 20xx, xx, x-x | 13
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ARTICLE
Dalton Transactions
2ˈ,6ˈ
72.0 (C2H), 70.3 (C5H), 54.3 (O
C
H3), 51.2 (C2ˈ,6ˈH2), 40.5 (C4ˈH),
C
H
overlapped), 3.05-2.95 (2 H, m, C6H''), 2.90 (2 H, br td, C4H),
ax
2.60 (2 H, br tt, C4ˈH), 1.86-1.83 (4 H, m, C3ˈ,5ˈHeq), 1.57-1.52 (4 H, m,
C3ˈ,5ˈHax) ppm. 13C{1H} NMR (100 MHz; DMSO-D6; 298 K):
207.2
(NCSS), 173.3 (C=O), 99.7 (C1H), 73.0 (C3H), 72.1 (C4H), 72.0 (C2H),
70.3 (C5H), 54.3 (OCH3), 46.1 (C2ˈ,6ˈH2), 40.7 (C4ˈH), 40.1 (C6H2), 28.0
(C3ˈ,5ˈH2) ppm.
40.1 (C6H2), 28.5 (C3ˈ,5ˈH2) ppm. 31P{1H} NMR (162 MHz; DMSO-
D6; 298 K): δ 36.5 (AuPPh3) ppm.
δ
Platinum(II)-dithiocarbamato complexes
[PtII(SSC-Inp-GlcN2)2] (Pt1). A DMF solution (2 mL) of Zn4 (15.2 mg,
0.02 mmol) was added dropwise under stirring to a DMF solution (2
mL) of (PPh4)[PtCl3(NH3)] (24.4 mg, 0.04 mmol) at room
temperature. The mixture was stirred for 16 h and then treated
with diethyl ether (40 mL). The resulting cloudy solution was stored
at 4°C for 1 h, leading to the formation of a yellow precipitate. The
precipitate was centrifuged and the bulk of supernatant discarded.
Conflicts of interest
To the best of our knowledge, there are no conflicts of interest
to declare.
The residue was subsequently washed with
a
1:1
Acknowledgements
methanol/dichloromethane solution (3×10 mL) and then dried
under vacuum over P2O5, yielding the title compound as a yellow
solid (12.2 mg, 35%). M.p. 195-198°C (dec.). Anal. (%) calcd. for
C28H46N4O12PtS4 (MM = 954.02 g mol-1): C, 35.25; H, 4.86; N, 5.87;
Financial support by NUI Galway (College of Science
Scholarship 2014 to AP; Millennium Fund Minor Project 2013
to LR), Irish Research Council (Postgraduate Scholarship
found: C, 35.14; H, 4.95; N, 5.81. FT-IR (CsI disk; 298 K): ṽmax 3401br GOIPG/2015/2961 to AP), and COST Action CM1105
“Functional metal complexes that bind to biomolecules” is
(ν, OH + NH overlapped), 1650 (ν, C=O (amide I)), 1523 (ν, N−CSS +
δip, CNH (amide II) overlapped), 1055br (ν, C−OH + C1−O−CH3
gratefully acknowledged.
overlapped), 1005 (νa, SCS), 577 (νs, SCS), 365 (νa, PtS4) cm-1. 1H
NMR (400 MHz; DMSO-D6; 298 K):
δ 7.84 (2 H, d, NH), 5.01 (2 H, d,
References
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C6H' overlapped), 3.49-3.40 (4 H, m, C3H + C6H'' overlapped), 3.33-
3.24 (6 H, m, C5H + C2ˈ,6ˈHax overlapped), 3.24 (6 H, s, OCH3), 3.15-
3.09 (2 H, m, C4H), 2.64 (2 H, tt, C4ˈH), 1.90-1.83 (4 H, br m, C3ˈ,5ˈHeq),
1.60-1.51 (4 H, br m, C3ˈ,5ˈHax) ppm. 13C{1H} NMR (100 MHz; DMSO-
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with diethyl ether (40 mL). The resulting cloudy solution was stored
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1007 (νa, SCS), 566 (νs, SCS), 350 (νa, PtS4) cm-1. H NMR (400 MHz;
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7.99 (2 H, dd, NH), 4.98 (2 H, d, C4OH), 4.83 (2
1
H, d, C3OH), 4.76 (2 H, d, C2OH), 4.51 (2 H, d, C1H, J1,2 = 3.3 Hz),
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Bayly, D. E. Green, I. Brudziñska, Y. Mikata, B. O. Patrick, M. J.
14 | Dalton Trans., 20xx, xx, x-x
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ARTICLE
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