Synthesis of new gold(I) thiolates containing amino acid moieties with potential biological interest

Article abstract of DOI:10.1021/ic4003803

The reaction of the gold(I) complex [Au(SpyCOOH)(PPh₃)], which contains nicotinic acid thiolate, with several amino acid esters such as glycine methyl ester or the enantiomerically pure l isomers of alanine methyl ester, phenylalanine methyl es

Full text of DOI:10.1021/ic4003803

Article
pubs.acs.org/IC
Synthesis of New Gold(I) Thiolates Containing Amino Acid Moieties
with Potential Biological Interest
Alejandro Gutierrez,† Javier Bernal,† M. Dolores Villacampa,† Carlos Cativiela,‡ Antonio Laguna,†
́
and M. Concepcion Gimeno*,†
́
†Departamento de Química Inorgan
Homogenea (ISQCH), CSIC-Universidad de Zaragoza, E-50009 Zaragoza, Spain
́
́
ica and Departamento de Química Organ
́
ica, Instituto de Síntesis Química y Catal
́
isis
‡
S
* Supporting Information
ABSTRACT: The reaction of the gold(I) complex [Au(SpyCOOH)(PPh3)],
which contains nicotinic acid thiolate, with several amino acid esters such as
glycine methyl ester or the enantiomerically pure L isomers of alanine methyl
ester, phenylalanine methyl ester, valine methyl ester, methionine methyl ester,
and proline methyl ester produces the gold(I) derivatives with the new thiolate
containing amino acid ester ligands [Au{SpyCONHCH(R)COOMe}(PPh3)].
The reaction of these amino acid ester derivatives with LiOH in methanol and
acidification with KHSO4 until pH 3−4 afford the corresponding acids, which are
water-soluble species. These amino acid compounds can be further coupled with
other amines, such as, for example, isopropylamine, to give the corresponding
amide derivatives. The species with glycine methyl ester and valine methyl ester
have been characterized by X-ray crystallography, showing, in the second case,
only one of the enantiomers, which proves that retention of the configuration after reaction occurs.
selective to abnormal cells.19 Not many gold(I) derivatives with
amino acids have been reported. Ligand-exchange reactions of
gold phosphine20 and gold cyano complexes21 with cysteine or
glutathione have been investigated. Gold(I) phosphine
complexes with N-substituted glycines have been reported.22
Human glutathione reductase (hGR) or thioredoxine reductase
are important targets for gold compounds,23 and the crystal
structure of a gold(I) complex with hGR24 and also a gold
protein with the AuPEt3 fragment bonded to a histidine rest25
have been reported and could give interesting insight in the
biological function of gold compounds. The reduction of a non-
emissive gold(III) complex with intracellular glutathione gives
the corresponding gold(I) glutathione derivative, which shows
promising anticancer activity, accompanied by the release of a
fluororescent ligand, thus serving in cellular thiol detection.26
Stoichiometric 1:1 complexes with amino acids have only been
described for cysteine-protected derivatives with phosphine or
N-heterocyclic carbenes,27 and thus we believe it is an interesting
goal in order to prepare gold(I) complexes with more
biologically compatible ligands.
INTRODUCTION
■
Thiolate metal complexes are very important in many areas of
research: (a) in bioinorganic chemistry mainly because of their
presence in very diverse metalloproteins and metalloenzymes,1,2
(b) in medicine as structural models for bioinorganic medicines3
or the use of gold thiolates in the treatment of arthritis,4,5 (c) in
material chemistry as precursors for chemical surface deposi-
tion of layers of metal or sulfides from the vapor phase,6−8 (d)
in catalysis for the chemistry relating to S−C bond cleavage
reactions and desulfurization,9 or carbon−heteroatom bond
formation,10 and (e) in nanoscience because thiolates stabilize
the formation of metal nanoparticles because of their outstanding
capability to form self-assembled monolayers.11,12 Noble metal
nanoparticles functionalized with biological thiolates are versatile
agents with several biomedical applications, including their
use in diagnostic assays,13 thermal ablation and radiotherapy
enhancement,14 or drug delivery.15
Following the success of the antiarthritic drug Auranofin, a
gold(I) thiolate bearing a carbohydrate moiety, as a good anti-
proliferative agent, many other gold(I) derivatives of carbo-
hydrates were prepared16 and tested for biological activity, as
well as others with thiolates derived from DNA bases, some of
them with antitumoral activity by themselves as the thiopurine
or thioguanine derivatives.17,18 In this sense, we think that the
synthesis of gold(I) thiolate complexes with thiolates bearing
amino acid moieties could be interesting in view of the possible
biological properties because the amino acids can serve as
good carriers to deliver the gold atom to the biological target
and because in tumoral cells the amino acid receptors are over-
expressed and, consequently, the complexes could be more
With this proposal, we first considered the nicotinic acid
thiolate gold complex [Au(SpyCOOH)(PPh3)], previously
synthesized by Nomiya et al., who demonstrated its anti-
bacterial activity.28 This complex possesses an acid moiety that
is adequate for functionalization with biological groups such as
the amino acids.
Received: February 14, 2013
© XXXX American Chemical Society
A
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a
Scheme 1. Synthesis of the Gold Thioamino Acid Derivatives
a
(i) Glycine methyl ester, DIPEA, PyBOP; (ii) alanine methyl ester, DIPEA, PyBOP; (iii) valine methyl ester, DIPEA, PyBOP; (iv) phenylalanine
methyl ester, DIPEA, PyBOP; (v) methionine methyl ester, DIPEA, PyBOP; (vi) proline methyl ester, DIPEA, PyBOP.
a
Here we report on the synthesis of gold thiolate complexes
functionalized with amino acid esters. In these cases, the gold
phosphine unit serves as a protecting group for the thiol because
in normal reactions coupling with amino acids is necessary to
protect the groups not involved in the reaction. The new thiolate
containing amino acid ester complexes can be easily converted
into their amino acid derivatives, and also coupling of the amino
acids with amines affords the amido derivatives. The character-
ization of the complexes demonstrates that the configuration of
the amino acid is retained upon reaction with the gold complex.
The ease of functionalization of these complexes opens a broad
field in the preparation of gold derivatives containing biological
molecules with potential medicinal properties.
Scheme 2. Synthesis of New Complexes
RESULTS AND DISCUSSION
■
a
(i) DIPEA, (ii) PyBOP, (iii) BzO−, and (iv) H2NCHRCOOMe.
Synthesis and Characterization. The phosphine thiolate
complex [Au(SpyCOOH)(PPh3)] can be readily prepared by a
procedure slightly different from that published,28 that is, by the
reaction of [AuCl(PPh3)] with mercaptoniconitic acid in acetone
in the presence of K2CO3, yielding the product in high yield.
This complex presents an acid moiety on the thiolate ligand that
can be used for coupling with amino acid esters such as glycine
methyl ester or the enantiomerically pure L isomers of alanine
methyl ester, valine methyl ester, phenylalanine methyl ester,
methionine methyl ester, and proline methyl ester. The reaction
in acetonitrile of the gold complex with diisopropylethylamine
(DIPEA), followed by the addition of benzotriazol-1-yloxytri-
pyrrolidinophosphonium hexafluorophosphate (PyBOP) and
the corresponding amino acid ester, gave after workup complexes
1−6 in good yield (Scheme 1). The gold phosphine unit acts
as a protecting group of the thiol because in normal reactions
coupling with amino acids is necessary to protect the groups not
involved in the reaction.
isolated and characterized by NMR spectroscopy, showing in
the H NMR spectra the resonances arising at the pyridine
1
group H1 as a multiplet, H2 as a doublet of doublets, and H3 as
a doublet of doublets, together with those of the benzotriazole
unit H4−H4′ as a doublet and the H5−H5′ signal overlapped
with the resonances of the phenylphosphine protons.
The amino acid ester conjugates were purified by column
chromatography and characterized by means of multinuclear
and 2D NMR spectroscopy. The H NMR spectra of glycine
methyl ester, alanine methyl ester, and valine methyl ester
show resonances of the corresponding amino acid ester, the
1
1
pyridine protons, and the phenylic protons. The H NMR
spectra of phenylalanine methyl ester, methionine methyl ester,
and proline methyl ester appear as a mixture of rotamers.
Normally, in amino acids and peptides, rotational freedom
exists around the NH−CαH, CαH−R, and CαH−CO bonds
(in this case, in the conformational analysis, the C(pyridine)−CO
and C(pyridine)−S bonds must also be taken into account).
However, if in the molecule is present an element that hinders or
prevents rotation (such as a protecting group or a bulky side
chain) freedom in rotation is lost and the molecule presents
different conformations that cannot pass each other by free
rotation, unless in the NMR time scale and at room temperature.
In the amino acid coupling reaction, PyBOP is used as the
carboxylic acid activating agent and DIPEA is used as a base to
produce nucleophilic attack of the amino group to the activated
carboxylic acid ester such as benzoxitriazole (which is very good
leaving group) to place the new amide bond in complexes 1−6.
The general mechanism, as well as the structure of the reagents,
is shown in Scheme 2. The reaction intermediate A has been
B
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1
Figure 1. H NMR spectra of complex 4 showing the presence of the two rotamers.
1
These conformations/configurations are called rotamers. The
signals have been assigned with the 2D correlation spectroscopy
(COSY) NMR spectra. For the phenylalanine derivative, the ratio
is 1:0.8, for the methionine 1:1, and for the proline 1:0.75. As an
example, the spectra of the phenylalanine derivative can be seen
in Figure 1. The proton for Cα of phenylalanine appears as a
doublet of triplets for each rotamer, with quite different chemical
shifts. The protons for the CβH2 group are diastereotopic and
appear also different for both rotamers with very different coupling
constants; for both rotamers, the signal is an ABX system, but
for rotamer B, the coupling constant is smaller than that for A.
In these resonances is where the ratio for both rotamers can be
calculated because others appear overlapped.
In the H NMR spectra, similar resonances for the amino
acids are observed, with the exception of the methyl group of
the ester precursor, which has disappeared. The protons for
the COOH group are not observed, but this usually happens,
with it being a mobile proton, and the observation depends on
the solvent and concentration. The resonance of the amide
protons appears at higher fields than those in the corresponding
precursors. In these compounds, no rotamers are observed,
with the exception of the proline derivative, probably because
of the less steric hindrance caused by removal of the methyl
group in the ester and because of the possibility of formation of
hydrogen bonds between the carboxylic group and the amide
proton, which would favor one of the configurations. All of the
resonances were assigned with the aid of 2D COSY NMR
experiments. The IR spectra show absorptions of the new
carboxylic group around 3400−2900 (s, br) and 1730 (s) cm−1.
The absorption for the carbonyl of the amide group appears
around 1660 (s) cm−1, and the one for the ester group has dis-
appeared. The mass spectra (ESI+) for these complexes show
the presence of the molecular peak [M]+ and the protonated
species [M + H]+ and the addition of a AuPPh3 fragment,
[M + AuPPh3]+.
The 31P{1H} NMR spectra present a unique resonance for all
of the complexes corresponding to the phosphorus of triphenyl-
phosphine; in all the cases; the chemical shift, as expected, is
very similar to that of the starting material. 13C{1H} NMR APT
spectra for compounds 1-6 show the resonances for the coupled
amino acid ester and the new amide group, as well as those of
the pyridine and triphenylphosphine moieties. The assignment
1
of the resonances was made with the H−13C heteronuclear
1
single quantum coherence and H−13C heteronuclear multiple-
The coupling of amino acid derivatives with an amine such
as isopropylamine produces the secondary amides (eq 2).
bond correlation experiments. The IR spectra present, among
others, absorptions for the amide unit at around 3200 (br, w)
and 1640 (s) and for the ester group at around 1740 (s). The
mass spectra (positive-mode electrospray ionization, ESI+)
present for all of the compounds the molecular peak [M+H]+,
together with the association fragment [M + AuPPh3]+.
The corresponding acid derivatives were obtained by
hydrolysis of amino acid esters using LiOH, which is less basic
than the normally used NaOH, trying to avoid racemization or
decomposition of the gold compounds. Thus, the reactions of
complexes 1−6 with LiOH, followed by neutralization with
KHSO4 (pH 3−4), to avoid protonation of the thiolate ligand
and then decomposition of the gold complex, lead to the acid
species 7−12 (eq 1).
The conditions used were the same as those used in the pre-
paration of the ester family. In this case, there is more steric
hindrance about the carboxylic acid, but the amine is more
nucleophilic than amino acid ester in the first reactions.
1
In the H NMR spectra of the new amide derivatives, it is
possible to observe the resonances for the two amide groups;
the one with the isopropyl group appears more shielded than
the first one probably because the isopropyl group is a better
donor group than the ester. In the complexes with a chiral
carbon center, the methyl groups of the isopropylamine appear
as inequivalent. The 31P{1H} NMR spectra present a unique
resonance for the phosphorus atom of triphenylphosphine with
C
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very small variation in the chemical shift, as observed for the
rest of the complexes. The IR spectra show that the absorption
arising at the carboxylic group has disappeared and the ones for
the amide groups appear around 3270 (w, br) and 1640 (s)
cm−1. In the mass spectra (ESI+), the molecular peak [M]+, the
protonated [M + H]+, and the one with an additional AuPPh3
fragment, [M + AuPPh3]+, are observed for all of the complexes.
Because we have used enantiomerically pure amino acid
esters, with the exception of glycine methyl ester, which is not
chiral, the angle of optical rotation has been measured in order
to know whether there is racemization after the reaction
conditions. For the amino acid ester derivatives, positive values
are found from 3.97 for PheOMe to 44.1 for ValOMe and a
negative value of −50.2 for ProOMe. The acid derivatives
present positive values from 5.9 (AlOH) to 30.0 (AlaOH) and
negative values of −18 to −56 for ProOH. The amide
derivatives present all negative values from −0.44 (ValNHiPr)
to −26.87 (ProNHiPr).
and the NH proton, with an O3···H2a distance of 2.211(8) Å
and an angle of 163.82(2)°.
The structure of complex 3 is shown in Figure 4. The com-
pound contains a chiral amino acid ester, valine methyl ester,
X-ray Structure Analysis. The crystal structures for the
glycine (1) and valine (3) ester derivatives have been established
by X-ray diffraction. Complex 1 crystallizes with two
independent molecules; one of those can be seen in Figure 2.
Figure 4. Diagram of 1 with 50% probability ellipsoids. Hydrogen
atoms (except NH and chiral CH) are omitted for clarity.
and crystallizes in the noncentrosymmetric group P212121.
Determination of the Flack parameter led to the conclusion
that only the S enantiomer is present in the molecule (such as
the enantiomerically pure valine methyl ester used). Again the
gold(I) center is found in a linear geometry with a P−Au−S
angle of 174.08(3)°. The distances Au−P and Au−S are
2.2515(7) and 2.3099(7) Å, respectively, which are very similar
to those in complex 1. The amide bond C6−N2 is 1.351(4) Å,
which is also on the same order as that of glycine methyl ester.
CONCLUSIONS
■
Synthesis of the thiolate containing amino acid ester species
[Au{SpyCONHCH(R)COOMe}(PPh3)] was achieved by
functionalization of the carboxylic group with amino acid esters
in the gold(I) thiolate complex [Au(SpyCOOH)(PPh3)], in
which the gold(I) center serves as a protecting group for the
thiol. The new complexes can be easily converted into the
water-soluble amino acid species by reaction with LiOH and
subsequent treatment with KHSO4. These amino acid species
are very versatile compounds that can be further functionalized
with other molecules through the acid moiety and, thus,
treatment with isopropylamine gave the corresponding amide
derivatives. With the exception of the glycine derivative, in all of
the cases enantiomerically pure L isomers have been used,
and the crystal structure of the valine methyl ester compound
shows the presence of the same S enantiomer and corroborates
that the configuration is retained upon reaction conditions. The
ease of functionalization of these complexes opens a broad field
in the preparation of gold derivatives containing biological
molecules with potential medicinal properties. These studies are
being conducted and will be published in due course.
Figure 2. Diagram of 1 with 50% probability ellipsoids. Hydrogen
atoms (except NH) are omitted for clarity.
The gold(I) centers in both molecules are in a linear environ-
ment with a P−Au−S angles of 178.13(9)° and 177.21(9)°,
respectively. The Au−P distances of 2.245(3) and 2.251(3) Å
and the Au−S bond lengths of 2.302(3) and 2.305(3) Å are
similar to those reported for the starting material, Au−P
of 2.254(2) Å and Au−S of 2.295(3) Å.27 In the thiolate
substituent, the new amide bond formed with glycine methyl
ester is observed with a C6−N2 distance of 1.334(12) Å.
There are several secondary bonds that can be considered as
hydrogen bonds in the molecule. Figure 3 represents the shortest
one between one of the oxygen atoms of glycine methyl ester
EXPERIMENTAL SECTION
■
Instrumentation. Carbon, hydrogen, and nitrogen analysis was
carried out with a Perkin-Elmer 2400 microanalyzer. Mass spectra
were recorded on a Bruker Esquire 3000 Plus, with the ESI technique,
and on a Bruker Microflex (matrix-assisted laser desorption ionization
time of flight). 1H, 13C{1H}, and 19F NMR, including 2D experiments,
were recorded at room temperature on a Bruker AVANCE 400 spectro-
meter (1H, 400 MHz; 13C, 100.6 MHz) or on a Bruker AVANCE II
300 spectrometer (1H, 300 MHz; 13C, 75.5 MHz), with chemical shifts
(δ, ppm) reported relative to the solvent peaks of the deuterated solvent.29
Figure 3. Hydrogen bonds in complex 1.
D
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Starting Materials. [AuCl(PPh3)]30 was prepared according to
published procedures and [Au(SpyCOOH)(PPh3)] with a slight variation
of the reported procedure.28 All other reagents were commercially
available. Solvents were used as received without purification or drying,
except for tetrahydrofuran, which was dried with a SPS solvent
purification system.
8.32 (dd, 1H, J = 4.6 and 2.0, H1), 8.28 (dd, 1H, J = 7.6 and 2.0, H3),
7.63−7.47 (m, 15H, Ar), 7.00 (dd, 1H, J = 7.6 and 4.6, H2), 4.78 (dd,
1H, J = 8.0 and 5.0, CαH), 3.73 (s, 3H), 2.34 (m, 1H, CβH), 1.09 (d,
6H, J = 6.8, CδH3). 31P NMR [CDCl3, 400 MHz, δ (ppm)]: 37.6.
13C NMR [CDCl3, 400 MHz, δ (ppm)]: 172.3 (COOMe), 166.5
(CONH), 164.7 (C, Py), 149.1 (CH, C1), 139.3 (CH, C3), 134.3 (d,
CH, J = 13.9, C5), 131.6 (d, CH, J = 2.1, C7), 130.0 (d, C, J = 47.3,
C4), 129.2 (C, Py), 129.1 (d, CH, J = 11.6, C6), 118.8 (CH, C2), 58.5
(CαH), 52.0 (OCH3), 31.2 (CβH), 19.4 (CχH3), 18.4 (CχH3). MS
(ESI+) m/z: [MH]+ 727.1 (calcd), 727.1 (found); [M + AuPPh3]+
1185.2. IR (cm−1): 3290 (w, br, NH), 1738 (s, COOMe), 1643
(s, CONH), 1570, 1522, and 1480 (w, Ar), 1099 and 1070 (s, COOMe),
744, 709, and 690 (w, Ar). Anal. Calcd for C30H30AuN2O3PS: C,
49.59; H, 4.16; N, 3.86; S, 4.41. Found: C, 49.35; H, 4.47; N, 4.04; S,
3.83. TLC: Rf = 0.4 (1:1 acetone/hexane). [α]D: +44.11 (c 1.0 g/mL,
CHCl3).
Synthesis of [Au(SpyCOOBzt)(PPh3)] (A). To a suspension of
[Au(SpyCOOH)(PPh3)] (0.613 g, 1 mmol) in acetonitrile (6 mL)
was added DIPEA (2.2 mmol). The mixture was stirred for 5 min at
room temperature, and then PyBOP was added (1.2 mmol), and the
resulting solution was stirred for an additional 45 min. Then the white
precipitate was filtered off, and the intermediate complex A was
1
obtained as a white solid. H NMR [CDCl3, 400 MHz, δ (ppm),
J (Hz)]: 8.41 (dd, 1H, J = 4.8 and 2.0, H1), 8.22 (dd, 1H, J = 7.6 and
2.0, H3), 8.07 (d, 1H, J = 8.4, H4), 7.75 (d, 1H, J = 7.8, H4′), 7.67−
7.61 and 7.54−7.48 (m, 15H, ArH), 7.52 (m, 1H, H5), 7.42 (m, 1H,
H5′), 7.06 (dd, 1H, J = 8.0 and 4.8, H2). 31P NMR [CDCl3, 400 MHz,
δ (ppm)]: 37.9. 13C NMR [CDCl3, 400 MHz, δ (ppm), J (Hz)]: 151.6
(CH, C1), 139.0 (CH, C3), 134.3 (d, CH, J = 14.0, C5), 131.7 (CH, C7),
129.1 (d, CH, J = 11.6, C6), 128.6 and 124.5 (CH, C10 and C10′),
120.3 and 109.4 (CH, C9 and C9′), 117.6 (CH, C2).
1
[Au(SpyCOPheOMe)(PPh3)] (4). Yield: 0.493 g, 63.7%. H NMR
[CDCl3, 400 MHz, δ (ppm), J (Hz)]: mixture of rotamers, ratio
1:0.8:9.33 (d, 1H, J = 6.8, CONH), 8.27−8.25 (m, 2H, H1 and H3),
7.64−7.48 (m, 15H), 7.33−7.18 (m, 5H), 6.99−6.96 (m, 1H, H2),
5.06 (A) and 3.75 (B) (dt, 1H, J = 13.6 and 6.8, J = 8.0 and 5.2, CαH),
3.72 and 3.69 (s, 3H), 3.28 and 3.22 (A) (ABX, 2H diastereotopic, J =
13.8 and 6.0, J = 14.0 and 6.8, CβH2), 3.10 and 2.86 (B) (ABX, 2H
diastereotopic, J = 13.6 and 5.2, J = 13.6 and 8.0, CβH2). 31P NMR
[CDCl3, 400 MHz, δ (ppm)]: 37.4. 13C NMR [CDCl3, 400 MHz, δ
(ppm), J (Hz)]: mixture of rotamers, 172.0 (COOMe), 166.1
(CONH), 165.8 (C, Py), 148.4 (CH, C1), 139.4 (CH, C3), 136.4
(C, C8), 134.3 (d, CH, J = 13.9, C5), 131.7 (d, CH, J = 2.2, C7), 130.1
(d, C, J = 64.0, C4), 129.5 and 129.2 (CH, R, C10), 129.1 (d, CH, J =
11.5, C6), 128.6 and 128.4 (CH, R, C9), 126.9 and 126.8 (CH, R,
C11), 118.3 (CH, C2), 55.8 (A) and 55.0 (B) (CaH), 52.1 (A) and
52.0 (B) (OCH3), 41.1 (A) and 38.2 (B) (CβH2). MS (ESI+) m/z:
[MH]+ 775.1 (calcd), 775.1 (found); [M + AuPPh3]+ 1233.2. IR
(cm−1): 3281 (w, br, NH), 1736 (s, COOMe), 1640 (s, CONH), 1571,
1518, 1495, and 1480 (w, Ar), 1100 and 1071 (s, CO), 745 and
709 (w, Ar). Anal. Calcd for C34H30AuN2O3PS: C, 52.72; H, 3.90; N,
3.62; S, 4.14. Found: C, 52.81; H, 3.68; N, 3.78; S, 4.01. TLC: Rf = 0.4
(1:1 acetone/hexane). [α]D: +3.97 (c 1.0 g/mL, CHCl3).
General Procedure for the Synthesis of Complexes 1−6. To
a suspension of [Au(SpyCOOH)(PPh3)] (0.613 g, 1 mmol) in
acetonitrile (6 mL) was added DIPEA (2.2 mmol). The mixture was
stirred for 5 min at room temperature, and then PyBOP was added
(1.2 mmol), and the resulting solution was stirred for an additional
45 min. To the resultant green solution was added dropwise and
at 0 °C a solution of the corresponding amino acid methyl ester
(1.5 mmol) in acetonitrile (4 mL) and DIPEA (1.5 mmol). After the
addition, the mixture was stirred for 48 h at room temperature.
Acetonitrile was evaporated, and dichloromethane (40 mL) was added.
This solution was washed with a saturated NaHCO3 solution in water
(3 × 15 mL) and a saturated solution of NaCl (3 × 15 mL). The organic
phase was dried over anhydrous MgSO4, filtered off, and evaporated
to dryness. The complexes were purified by column chromatography of
silica gel using as the eluent a mixture of 3:7 acetone/hexane.
1
[Au(SpyCOGlyOMe)(PPh3)] (1). Yield: 0.475 g, 69.4%. H NMR
[CDCl3, 400 MHz, δ (ppm), J (Hz)]: 9.17 (s, br, 1H, CONH), 8.33
(dd, 1H, J = 4.6 and 1.6, H1), 8.29 (dd, 1H, J = 8.0 and 1.6, H3) 7.62−
7.48 (m, 15H, Ar), 7.02 (dd, 1H, J = 8.0 and 4.6, H2), 4.30 (d, 2H,
J = 4.8, CαH2), 3.78 (s, 3H). 31P NMR [CDCl3, 400 MHz, δ (ppm)]:
37.6. 13C NMR [CDCl3, 400 MHz, δ (ppm), J (Hz)]: 170.3 (COOMe),
166.8 (CONH), 164.7 (C, Py), 149.3 (CH, C1), 139.3 (CH, C3),
134.3 (d, CH, J = 13.9, C5), 131.7 (CH, C7), 129.7 (d, C, J = 56.1,
C4), 129.2 (d, CH, J = 11.4, C6), 118.9 (CH, C2), 52.3 (OCH3), 42.1
(CαH2). MS (ESI+) m/z: [MH]+ 685.0 (calcd), 684.9 (found); [M +
AuPPh3]+ 1143.3. IR (cm−1): 3360 (br, w, NH), 1736 (s, COOMe),
1645 (s, CONH), 1573, 1517, and 1480 (w, Ar), 1099 and 1064 (s,
C−O), 746, 709, and 690 (w, Ar). Anal. Calcd for C27H24AuN2O3PS:
C, 47.38; H, 3.53; N, 4.09; S, 4.68. Found: C, 46.98; H, 3.92; N, 4.04;
S, 4.39. TLC: Rf = 0.4 (1:1 acetone/hexane).
1
[Au(SpyCOMetOMe)(PPh3)] (5). Yield: 0.463 g. 61.1%. H NMR
[CDCl3, 400 MHz, δ (ppm), J (Hz)]: mixture of rotamers, ratio
1:0.75:9.05 (d, 1H, J = 7.6), 8.30 (dd, 1H, J = 4.8 and 2.0, H1), 8.21
(dd, 1H, J = 8.0 and 2.0, H3), 7.60−7.45 (m, 15H), 6.98 (dd, 1H, J =
8.0 and 4.8, H2), 4.94 (A) and 3.58 (B) (“dt”, 1H, J = 7.6 and 5.0, J =
8.3 and 4.9, CαH), 3.73 and 3.71 (s, 3H), 2.68 (B) and 2.63−2.58 (A)
(ddd and m, 2H, J = 8.4, 6.7, and 1.6, CχH2), 2.28 (A) and 2.16 (B)
(dt and m, 2H diastereotopic, J = 8.6, 7.6, and 5.0, CβH2), 2.01 (A)
and 1.76 (B) (m, 2H diastereotopic, CβH2), 2.08 and 2.08 (s, 3H). 31
P
NMR [CDCl3, 400 MHz, δ (ppm)]: 37.6. 13C NMR [CDCl3, 400
MHz, δ (ppm), J (Hz)]: mixture of rotamers, 176.1 and 172.2
(COOMe), 166.4 and 164.6 (CONH), 164.7 (C, Py), 149.2 (CH, C1),
139.0 (CH, C3), 134.2 (d, CH, J = 13.9, C5), 131.6 (CH, C7), 129.9
(d, C, J = 41.2, C4), 129.1 (d, CH, J = 11.5, C6), 118.8 (CH, C2), 53.1
and 52.0 (CαH), 52.3 and 52.3 (OCH3), 33.8 (A) (CχH2) and 30.1 (B)
(CχH2), 31.7 (A) (CβH2) and 30.4 (B) (CβH2), 15.4 (CH3). MS
(ESI+) m/z: [MH]+ 759.1 (calcd), 759.1 (found); [M + AuPPh3]+
1217.0. IR (cm−1): 1734 (s, COOMe), 1645 (s, CONH), 1571, 1522,
and 1480 (w, Ar), 1100 and 1071 (s, COOMe), 746 and 709 (w, Ar).
Anal. Calcd for C30H30AuN2O3PS2: C, 47.50; H, 3.99; N, 3.69; S, 8.45.
Found: C, 47.41; H, 4.16; N, 3.81; S, 8.48. TLC: Rf = 0.4 (1:1 acetone/
hexane). [α]D: +22.4 (c 1.0 g/mL, CHCl3).
1
[Au(SpyCOAlaOMe)(PPh3)] (2). Yield: 0.473 g, 67.7%. H NMR
[CDCl3, 400 MHz, δ (ppm), J (Hz)]: 9.63 (d, 1H, J = 5.2, CONH),
8.38 (dd, 1H, J = 7.6 and 2.0, H1), 8.19 (dd, 1H, J = 5.2 and 2.0, H3),
7.63−7.47 (m, 15H, Ar), 6.98 (dd, 1H, J = 7.6 and 5.2, H2), 4.80 (“q”,
1H, J = 7.2 Hz, CαH), 3.76 (s, 3H), 1.57 (d, 3H, J = 7.2, CβH3). 31P
NMR [CDCl3, 400 MHz, δ (ppm)]: 37.6. 13C NMR [CDCl3, 400
MHz, δ (ppm), J (Hz)]: 173.3 (COOMe), 165.9 (CONH), 165.6
(C, Py), 148.4 (CH, C1), 139.4 (CH, C3), 134.2 (d, CH, J = 14.1, C5),
131.5 (d, CH, J = 2.3, C7), 130.4 (C, Py), 129.7 (d, C, J = 55.2, C4),
129.1 (d, CH, J = 11.5, C6), 118.3 (CαH, C2), 52.4 (OCH3), 49.1
(CαH), 18.1 (CβH3). MS (ESI+) m/z: [MH]+ 699.1 (calcd), 699.0
(found); [M + AuPPh3]+ 1157.1. IR (cm−1): 3273 (br, w, NH), 1739
(s, COOMe), 1639 (s, CONH), 1570, 1523, and 1479 (w, Ar), 1098
and 1069 (s, CO), 744, 709, and 690 (w, Ar). Anal. Calcd for
C28H26AuN2O3PS: C, 48.14; H, 3.75; N, 4.01; S, 4.59. Found: C,
48.07; H, 3.81; N, 4.09; S, 4.32. TLC: Rf = 0.4 (1:1 acetone/hexane).
[α]D: +36.16 (c 1.0 g/mL, CHCl3).
1
[Au(SpyCOProOMe)(PPh3)] (6). Yield: 0.437 g, 60.4%. H NMR
[CDCl3, 400 MHz, δ (ppm), J (Hz)]: mixture of rotamers, ratio
1:0.75:8.24 (A) and 8.20 (B) (dd, 1H, J = 5.0 and 1.8, J = 5.0 and 1.8,
H1), 7.58−7.35 (m, 15H, Ar), 7.43 and 7.29 (m and dd, 1H, J = 7.4 and
1.8, H3), 6.86 (A) and 6.80 (B) (dd, 1H, J = 7.4 and 5.0, J = 7.6 and 4.8,
H2), 4.60 and 4.60 (dd, 1H, J = 8.8 and 3.6, CαH), 3.69 (A) and 3.43
(B) (s, 3H), 3.66 (“dd”, 2H, J = 6.0 and 2.0, CδH2), 2.30 (B) and 2.21
and 2.03 (A) (CβH2, m, 2H each), 1.97 and 1.90 (CχH2, m, 2H each).
31P NMR [CDCl3, 400 MHz, δ (ppm)]: 37.8. 13C NMR [CDCl3, 400
MHz, δ (ppm), J (Hz)]: mixture of rotamers, 173.0 and 172.7 (COOMe),
1
[Au(SpyCOValOMe)(PPh3)] (3). Yield: 0.485 g, 66.8%. H NMR
[CDCl3, 400 MHz, δ (ppm), J (Hz)]: 9.09 (d, 1H, J = 8.0, CONH),
E
dx.doi.org/10.1021/ic4003803 | Inorg. Chem. XXXX, XXX, XXX−XXX

Inorganic Chemistry
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1
168.7 and 168.4 (CONH), 162.6 and 162.3 (C, Py), 148.6 and 148.5
(CH, C1), 134.9 (CH, C3), 134.1 and 132.0 (d, CH, J = 14.2, J = 9.9, C5),
131.9 and 131.4 (d, CH, J = 2.7, J = 2.3, C7), 134.5 and 129.9 (d, C, J =
27.9, J = 52.4, C4), 129.1 and 128.4 (d, CH, J = 11.3, J = 12.2, C6), 118.1
and 117.9 (CH, C2), 60.0 and 58.5 (CαH), 52.1 and 51.9 (OCH3), 47.8
and 46.2 (CδH2), 31.2 and 29.6 (CβH2), 24.8 and 23.0 (CχH2). MS (ESI+)
m/z: [MH]+ 725.1 (calcd), 725.1 (found); [M + AuPPh3]+ 1183.1. IR
(cm−1): 1738 (s, COOMe), 1629 (s, CONH), 1570, 1545, and 1479
(w, Ar), 1097 and 1093 (s, COOMe), 746 and 709 (w, Ar). Anal. Calcd
for C30H28AuN2O3PS: C, 49.73; H, 3.90; N, 3.87; S, 4.43. Found: C,
49.67; H, 4.06; N, 3.78; S, 4.30. TLC: Rf = 0.4 (1:1 acetone/hexane).
[α]D: −50.2 (c 1.0 g/mL, CHCl3).
[Au(SpyCOPheOH)(PPh3)] (10). Yield: 0.542 g, 71.3%. H NMR
[CDCl3, 400 MHz, δ (ppm), J (Hz)]: 9.25 (d, 1H, J = 5.2), 8.30−8.29
(m, 1H, H1), 8.19 (d, 1H, J = 7.6, H3), 7.60−7.44 (m, 15H, Ar), 7.22
(m, 5H), 6.97 (dd, 1H, J = 7.4 and 4.6, H2), 4.89 (“dd”, 1H, J = 12.1
and 6.0, CαH), 3.38 and 3.21 (ABX, 2H diastereotopic, J = 13.9 and
5.2, J = 13.9 and 7.1, CβH2). 31P NMR [CDCl3, 400 MHz, δ (ppm)]:
37.1. 13C NMR [CDCl3, 400 MHz, δ (ppm), J (Hz)]: 171.8 (COOH),
167.7 (CONH), 164.6 (C, Py), 149.4 (CH, C1), 139.1 (CH, C3),
136.7 (C, C8), 134.2 (d, CH, J = 13.9, C5), 131.7 (CH, C7), 129.8 (C,
C4), 129.7 (CH, R, C10), 129.2 (d, CH, J = 11.5, C6), 128.4 (CH, R,
C9), 126.7 (CH, R, C11), 118.9 (CH, C2), 55.9 (CαH), 37.0 (CβH2).
MS (ESI+) m/z: [MH]+ 761.1 (calcd), 761.1 (found); [M + AuPPh3]+
1219.2. IR (cm−1): 3400−2900 (br, COOH), 1725 (s, COOH), 1636
(s, CONH), 1568 and 1479 (w, Ar), 1096 and 1065 (CO, s), 743 and
710 (w, Ar). Anal. Calcd for C33H28AuN2O3PS: C, 52.11; H, 3.71; N,
3.68; S, 4.22. Found: C, 52.04; H, 4.00; N, 3.69; S, 4.18. [α]D: −7.64
(c 1.0 g/mL, CHCl3).
General Procedure for the Synthesis of Complexes 7−12. To
a suspension of the corresponding complexes 1−6 (1 mmol) in
methanol (20 mL) was added LiOH (0.480 g, 20 mmol). The mixture
was stirred at room temperature for a period between 24 and 48 h.
The reaction was followed by thin-layer chromatography (TLC) and
was complete when the starting compound [Rf = 0.4 (1:1 acetone/
hexane)] was strongly retained at the origin of TLC [Rf = 0
(1:1 acetone/hexane)]. At this point, methanol was evaporated and
the product dissolved in water. The resulting white solution was
acidified dropwise with a saturated solution of KHSO4 until a slightly
acidic pH (3−4). Then the solution was extracted three times with
dichloromethane, and the organic phase was dried over anhydrous
MgSO4, filtered off, and evaporated to yield pure compounds 7−12.
1
[Au(SpyCOMetOH)(PPh3)] (11). Yield: 0.517 g, 69.5%. H NMR
[CDCl3, 400 MHz, δ (ppm), J (Hz)]: 9.12−9.10 (m, 1H), 8.30−8.29
(m, 1H, H1), 8.18 (d, 1H, J = 7.4, H3), 7.58−7.41 (m, 15H, Ar),
6.97 (dd, 1H, J = 7.4 and 4.8, H2), 4.74 (“dd”, 1H, J = 11.2 and 6.0,
CαH), 2.70 (“t”, 2H, J = 7.2, CχH2), 2.32 and 2.16 (td and m, 2H
diastereotopic, J = 13.2 and 7.6, CβH2), 2.04 (s, 3H). 31P NMR
[CDCl3, 400 MHz, δ (ppm)]: 36.3. 13C NMR [CDCl3, 400 MHz, δ
(ppm), J (Hz)]: 170.9 (COOH), 167.7 (CONH), 164.4 (C, Py), 149.3
(CH, C1), 139.1 (CH, C3), 134.2 (d, CH, J = 13.8, C5), 131.7 (d, CH,
J = 0.8, C7), 130.0 (d, C, J = 59.7, C4), 129.2 (d, CH, J = 11.5, C6),
119.0 (CH, C2), 53.8 (CαH), 31.0 (CβH2), 30.3 (CχH2), 15.4 (CH3).
MS (ESI+) m/z: [MH]+ 745.1 (calcd), 745.1 (found); [M + AuPPh3]+
1203.1. IR (cm−1): 3400−3000 (br, COOH), 1719 (s, COOH), 1639
(s, CONH), 1571, 1515, and 1479 (w, Ar), 1098 and 1069 (s, CO),
743 and 710 (w, Ar). Anal. Calcd for C29H28AuN2O3PS2: C, 46.78;
H, 3.79; N, 3.76; S, 8.61. Found: C, 46.62; H, 3.82; N, 3.71; S, 8.43.
[α]D: +8.19 (c 1.0 g/mL, CHCl3).
1
[Au(SpyCOGlyOH)(PPh3)] (7). Yield: 0.514 g, 76.8%. H NMR
[CDCl3, 400 MHz, δ (ppm), J (Hz)]: 8.74 (m, 1H), 8.21 (dd, 1H, J =
4.8 and 2.0, H1), 8.00 (dd, 1H, J = 7.6 and 2.0, H3), 7.53−7.37 (m,
15H, Ar), 6.89 (dd, 1H, J = 7.6 and 4.8, H2), 4.03 (d, 2H, J = 4.8,
CαH). 31P NMR [CDCl3, 400 MHz, δ (ppm)]: 37.4. 13C NMR
[CDCl3, 400 MHz, δ (ppm), J (Hz)]: 171.9 (COOH), 167.1
(CONH), 163.3 (C, Py), 148.9 (CH, C1), 138.4 (CH, C3), 134.2 (d,
CH, J = 13.6, C5), 131.8 (CH, C7), 129.2 (d, CH, J = 10.9, C6), 129.2
(d, C, J = 54.9, C4), 118.9 (CH, C2), 43.4 (CaH2). MS (ESI−) m/z:
671.1 (calcd), 671.1 (found); [M + AuPPh3]+ 1129.2. IR (cm−1):
3400−2900 (s, br, COOH), 1728 (s, COOH), 1657 (s, CONH), 1574,
1548, and 1479 (w, Ar), 1102 and 1053 (CO, s), 743 and 709 (w, Ar).
Anal. Calcd for C26H22AuN2O3PS: C, 46.58; H, 3.31; N, 4.18; S, 4.78.
Found: C, 46.62; H, 3.42; N, 4.15; S, 4.60.
1
[Au(SpyCOProOH)(PPh3)] (12). Yield: 0.485 g, 68.3%. H NMR
[CDCl3, 400 MHz, δ (ppm), J (Hz)]: mixture of rotamers, ratio
1:0.95:8.29 (A) and 1:0.95:7.98 (B) (dd, 1H, J = 4.8 and 1.8, J = 5.2
and 1.8, H1), 7.49−7.37 (m, 15H, Ar), 7.52 and 7.43 (m, 1H, H3),
6.92 (A) and 6.75 (B) (dd, 1H, J = 7.6 and 4.8, J = 7.6 and 5.2, H2),
4.69 (A) and 4.30 (B) (dd, 1H, J = 8.2 and 3.4, J = 8.2 and 2.2, CαH),
3.71 and 3.56 (rotamer A, H diastereotopic) and 3.47 (rotamer B)
(“td” (A) and “q” (B), 2H, J = 11.6 and 8.0 (A), J = 7.0 (B), CδH2),
2.41 and 2.05 (rotamer A, H diastereotopic) and 2.06 (B) (m, 2H,
CβH2) and 1.92 (A) and 1.73 (B) (m, 2H, CχH2). 31P NMR [CDCl3,
400 MHz, δ (ppm)]: 36.6. 13C NMR [CDCl3, 400 MHz, δ (ppm),
J (Hz)]: mixture of rotamers, 175.7 (COOH), 168.3 (CONH), 159.9
(C, Py), 149.1 and 148.1 (CH, C1), 135.8 (CH, C3), 135.5 and 129.3
(d,C, J = 54.0, C4), 134.0 (d, CH, J = 13.8, C5), 131.8 (CH, C7), 129.3
(d, CH, J = 11.2, C6), 119.4 and 118.4 (CH, C2), 61.8 and 60.4
(CαH), 48.7 and 46.0 (CδH2), 31.6 and 28.0 (CβH2), 24.7 and
23.0 (CχH2). MS (ESI+) m/z: [MH]+ 711.1 (calcd), 711.1 (found);
[M + AuPPh3]+ 1169.1. IR (cm−1): 3500−3100 (br, COOH), 1608
(s, CONH), 1568 and 1479 (w, Ar), 1097 and 1093 (s, CO), 744 and
708 (w, Ar). Anal. Calcd for C29H26AuN2O3PS: C, 49.02; H, 3.69; N,
3.94; S, 4.51. Found: C, 49.14; H, 4.04; N, 3.95; S, 4.81. [α]D: −18.56
(c 1.0 g/mL, CHCl3).
1
[Au(SpyCOAlaOH)(PPh3)] (8). Yield: 0.544 g, 79.5%. H NMR
[CDCl3, 400 MHz, δ (ppm), J (Hz)]: 9.25 (d, 1H, J = 5.6), 8.33 (dd,
1H, J = 4.6 and 2.0, H1), 8.24 (dd, 1H, J = 7.6 and 2.0, H3), 7.59−7.42
(m, 15H), 7.02 (dd, 1H, J = 7.6 and 4.6, H2), 4.65 (“q”, 1H, J = 6.8,
CαH), 1.59 (d, 3H, J = 6.8, CβH3). 31P NMR [CDCl3, 400 MHz, δ
(ppm)]: 37.2. 13C NMR [CDCl3, 400 MHz, δ (ppm), J (Hz)]: 173.6
(COOH), 168.3 (CONH), 164.6 (C, Py), 149.6 (CH, C1), 139.1 (CH,
C3), 134.2 (d, CH, J = 13.8, C5), 131.7 (d, CH, J = 1.3, C7), 129.6 (C,
Py), 129.3 (d, C, J = 57.7, C4), 129.2 (CH, J = 11.5, C6), 119.1 (CH,
C2), 50.5 (CαH), 16.9 (CH3). MS (ESI+) m/z: [MH]+ 685.1 (calcd),
685.0 (found); [M + AuPPh3]+ 1143.1. IR (cm−1): 3400−2900 (s, w,
COOH), 1731 (s, COOH), 1637 (s, CONH), 1570, 1519, and 1479
(w, Ar), 1098 and 1069 (CO, s) 743 and 709 (w, Ar). Anal. Calcd for
C27H24AuN2O3PS: C, 47.38; H, 3.53; N, 4.09; S, 4.68. Found: C,
47.60; H, 3.90; N, 3.78; S, 4.72. [α]D: +5.9 (c 1.0 g/mL, CHCl3).
1
[Au(SpyCOValOH)(PPh3)] (9). Yield: 0.600 g, 84.3%. H NMR
[CDCl3, 400 MHz, δ (ppm), J (Hz)]: 9.32 (d, 1H, J = 7.2), 8.35 (dd,
1H, J = 4.8 and 2.0, H1), 8.31 (dd, 1H, J = 7.8 and 2.0, H3), 7.61−7.44
(m, 15H, Ar), 7.02 (dd, 1H, J = 7.8 and 4.8, H2), 4.64 (dd, 1H, J = 7.2
and 5.2, CαH), 2.52 (m, 1H, CβH), 1.15 (d, 3H, J = 5.2, CχH3), 1.13 (d,
3H, J = 5.2, CχH3). 31P NMR [CDCl3, 400 MHz, δ (ppm)]: 36.4. 13C
NMR [CDCl3, 400 MHz, δ (ppm), J (Hz)]: 174.0 (COOH), 167.6
(CONH), 164.6 (C, Py), 149.4 (CH, C1), 139.5 (CH, C3), 134.3
(d, CH, J = 14.0, C5), 131.7 (d, CH, J = 2.3, C7), 129.9 (C, C4), 129.8
(C, Py), 129.2 (d, CH, J = 11.5, C6), 119.0 (CH, C2), 59.4 (CαH),
30.2 (CβH2), 19.6 (CχH3), 18.3 (CχH3). MS (ESI+) m/z: [MH]+
713.1 (calcd), 713.1 (found); [M + AuPPh3]+ 1171.4. IR (cm−1):
3400−3200 (br, COOH), 1635 (s, CONH), 1565 and 1479 (w, Ar),
1097 and 1070 (s, CO), 743 and 708 (w, Ar). Anal. Calcd for
C29H28AuN2O3PS: C, 48.88; H, 3.96; N, 3.93; S, 4.50. Found: C,
48.71; H, 3.98; N, 3.95; S, 4.51. [α]D: +30.0 (c 1.0 g/mL, CHCl3).
General Procedure for the Synthesis of Complexes 13−18.
To a solution of the corresponding acid derivatives 6−12 (1 mmol) in
acetonitrile (10 mL) was added DIPEA (2.2 mmol). The mixture
was stirred at room temperature for 15 min, and PyBOP was added
(1.2 mmol). After 15 min, isopropylamine was added (1.1 mmol), and
then the mixture was stirred for 36 h. The solvent was evaporated, and
the products were purified by silica gel column chromatography using
as the eluent 1:1 acetone/hexane.
1
[Au(SpyCOGlyNHiPr)(PPh3)] (13). Yield: 0.284 g, 40%. H NMR
[CDCl3, 400 MHz, δ (ppm), J (Hz)]: 8.44 (“t”, 1H, CONHGly),
8.24 (dd, 1H, J = 5.0 and 2.0, H1), 8.07 (dd, 1H, J = 7.6 and
2.0, H3), 7.52−7.42 (m, 15H, Ar), 6.97 (dd, 1H, J = 7.6 and 5.0,
H2), 6.70 (d, 1H, J = 6.4, CONHiPro), 4.10 (d, 2H, J = 6.0, CαH2),
4.03 (septsex, 1H, J = 6.8, CiProH), 1.10 (d, 6H, J = 6.8, CiProH3).
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dx.doi.org/10.1021/ic4003803 | Inorg. Chem. XXXX, XXX, XXX−XXX

Inorganic Chemistry
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31P NMR [CDCl3, 400 MHz, δ (ppm)]: 37.3. 13C NMR [CDCl3, 400
MHz, δ (ppm), J (Hz)]: 168.2 (CONHiPro), 167.2 (CONHGly), 164.7
(C, Py), 148.2 (CH, C1), 139.2 (CH, C3), 134.3 (d, CH, J = 12.8, C6),
131.9 (d, CH, J = 4.4, C7), 129.3 (d, CH, J = 14.7, C5), 129.2 (C, J =
57.2, C4), 118.7 (CH, C2), 44.1 (CαH2), 41.7 (CiProH), 22.7 (CiProH3).
MS (ESI−) m/z: 712.1 (calcd), 712.1 (found); [M + AuPPh3]+ 1170.2.
IR (cm−1): 3278 (NH, br), 1637 (s, CONH), 1571 and 1480 (m, Ar),
1098 and 1071 (m, CO), 745 and 709 (w, Ar). Anal. Calcd for
C29H29AuN3O2PS: C, 48.95; H, 4.11; N, 5.91; S, 4.51. Found: C,
48.60; H, 4.21; N, 5.82; S, 4.82. TLC: Rf = 0.2 (1:1 acetone/hexane).
[Au(SpyCOAlaNHiPr)(PPh3)] (14). Yield: 0.308 g, 42.5%. 1H
NMR [CDCl3, 400 MHz, δ (ppm), J (Hz)]: 8.34 (d, 1H, J = 2.0,
CONHAla), 8.32 (dd, 1H, J = 8.8 and 2.0, H1), 8.10 (dd, 1H, J = 7.6
and 2.0, H3), 7.62−7.45 (m, 15H), 7.01 (dd, 1H, J = 7.6 and 4.8, H2),
6.85 (d, 1H, J = 6.8, CONHiPro), 4.72 (“q”, 1H, J = 7.4, CαH), 4.06
(“dq”, 1H, J = 6.6 and 13.2, CiProH), 1.51 (d, 3H, J = 7.2, CβH3), 1.16
(d, 3H, J = 6.8, CiProH3), 1.15 (d, 3H, J = 6.8, CiProH3). 31P NMR
[CDCl3, 400 MHz, δ (ppm)]: 35.9. 13C NMR [CDCl3, 400 MHz, δ
(ppm), J (Hz)]: 171.2 (CONHiPro), 167.1 (CONHAla), 164.9 (C, Py),
149.0 (CH, C1), 138.7 (CH, C3), 134.3 (d, CH, J = 14.2, C5), 131.6
(d, CH, J = 2.3, C7), 131.1 (C, Py), 129.7 (d, C, J = 73.3, C4), 129.2
(d, CH, J = 11.5, C6), 118.7 (CH, C2), 50.0 (CαH), 41.5 (CiProH), 22.7
(CiProH3), 17.7 (CβH3). MS (ESI+) m/z: [MH]+ 726.1 (calcd), 726.1
(found); [M + AuPPh3]+ 1184.2. IR (cm−1): 3280 (br, CONH), 1637
(s, CONH), 1571, 1512, and 1480 (w, Ar), 1099 and 1069 (w, CO),
745 and 709 (w, Ar). Anal. Calcd for C30H31AuN3O2PS: C, 49.66; H,
4.31; N, 5.79; S, 4.42. Found: C, 49.48; H, 4.37; N, 5.51; S, 4.32. [α]D:
−1.88 (c 0.5 g/mL, CHCl3). TLC: Rf = 0.2 (1:1 acetone/hexane).
7.63−7.46 (m, 15H), 7.02 (dd, 1H, J = 7.6 and 4.8, H2), 6.79 (d, 1H,
J = 7.2, CONHiPro), 4.82 (“dt”, 1H, J = 8.2 and 5.1, CαH), 4.07 (“dt”,
1H, J = 13.2 and 6.6, CiProH), 2.66 (“t”, 2H, J = 7.5, CχH2), 2.38−2.30
and 2.14−2.03 (m, 2H diastereotopic, CβH2), 2.11 (s, 3H), 1.16 (d,
3H, J = 6.4, CiProH3), 1.15 (d, 3H, J = 6.4, CiProH3). 31P NMR [CDCl3,
400 MHz, δ (ppm)]: 37.3. 13C NMR [CDCl3, 400 MHz, δ (ppm),
J (Hz)]: 170.0 (CONHiPro), 167.3 (CONHMet), 164.3 (C, Py),
149.3 (CH, C1), 138.7 (CH, C3), 134.3 (d, CH, J = 14.0, C5), 131.7
(d, CH, J = 2.3, C7), 130.3 (d, C, J = 70.1, C4), 129.2 (d, CH, J = 11.5,
C6), 118.9 (CH, C2), 53.4 (CαH), 41.6 (CiProH), 31.1 (CβH2),
30.5 (CχH2), 22.7 (CiProH3), 15.3 (CH3). MS (ESI+) m/z: [MH]+
786.1 (calcd), 786.1 (found); [M + AuPPh3]+ 1244.2. IR (cm−1):
3263 (br, CONH), 1636 (s, CONH), 1570, 1512, and 1480 (w, Ar),
1099 and 1070 (s, CO), 745 and 709 (w, Ar). Anal. Calcd for
C32H35AuN3O2PS2: C, 48.92; H, 4.49; N, 5.35; S, 8.16. Found: C,
49.09; H, 4.38; N, 5.13; S, 8.01. [α]D: −2.66 (c 0.5 g/mL, CHCl3).
1
[Au(SpyCOProNHiPr)(PPh3)] (18). Yield: 0.318, 42.3%. H NMR
[CDCl3, 400 MHz, δ (ppm), J (Hz)]: mixture of rotamers, ratio 1:0.1;
8.34 (A) and 8.29 (B) (dd, 1H, J = 4.8 and 2.0, J = 4.8 and 2.0, H1),
7.62−7.41 (m, 15H), 7.58−7.55 (m, 1H, CONHiPro), 7.46−7.26 (A)
and 7.33−7.19 (B) (m, 1H, H3), 6.99 (A) and 6.89 (B) (dd, 1H, J =
7.6 and 4.8, H2), 4.71 (dd, 1H, J = 7.8 and 2.4, CαH), 4.08 (“dt”, 1H,
J = 13.4 and 6.7, CiProH), 3.67 and 3.15 (“td” and “q”, 2H, J = 13.3 and
6.6, J = 7.4, CδH2), 2.28 and 2.17 (diastereotopic H, m, 2H, CβH2),
1.89 (m, 2H, CχH2), 1.20 (d, 3H, J = 6.8, CiProH3), 1.18 (d, 3H, J = 6.8,
CiProH3). 31P NMR [CDCl3, 400 MHz, δ (ppm)]: 37.5. 13C NMR
[CDCl3, 400 MHz, δ (ppm), J (Hz)]: mixture of rotamers, 170.4
(CONHiPro), 162.0 (CONHPro), 149.0 (CH, C1), 134.3 (d, CH, J =
13.4, C5), 133.9 (CH, C3), 131.7 (CH, C7), 129.8 (C, C4), 129.2 (d,
CH, J = 11.5, C6), 118.7 (CH, C2), 60.6 and 55.6 (CαH), 48.4 and
43.6 (CδH2), 41.7 (CiProH), 29.3 (CβH2), 24.5 (CχH2), 22.9 (CiProH3),
22.7 (CiProH3). HRMS (ESI+) m/z: [MH]+ 752.1511 (calcd),
752.1275 (found); [M + AuPPh3]+ 1210.2. IR (cm−1): 3319 (br,
CONH), 1635 (s, CONH), 1572, 1547, and 1480 (w, Ar), 1099 and
1073 (s, CO), 747, 710, and 691 (w, Ar). Anal. Calcd for
C32H33AuN3O2PS: C, 51.13; H, 4.43; N, 5.59; S, 4.27. Found: C,
51.36; H, 4.45; N, 5.95; S, 4.44. [α]D: −26.87 (c 1.0 g/mL, CHCl3).
Crystallography. Crystals were mounted in an inert oil on glass
fibers and transferred to the cold gas stream of APEX SMART (1) and
Xcalibur Oxford Diffraction (3) diffractometers equipped with a low-
temperature attachment. Data were collected using monochromated
Mo Kα radiation (λ = 0.71073 Å). The scan type was ω. Absorption
correction based on multiple scans was applied with the program
SADABS31 (1) or using spherical harmonics implemented in the
SCALE3 ABSPACK32 scaling algorithm (3). The structures were solved
by direct methods and refined on F2 using the program SHELXL-97.33
All non-hydrogen atoms were refined anisotropically. For complex 1,
hydrogen atoms were included in calculated positions and refined using
a riding model; for complex 3, the hydrogen atoms were located in the
difference map. Refinements were carried out by full-matrix least
squares on F2 for all data. Further details of the data collection and
refinement and complete bond lengths and angles are given in the
Supporting Information.
1
[Au(SpyCOValNHiPr)(PPh3)] (15). Yield: 0.331, 44%. H NMR
[CDCl3, 300 MHz, δ (ppm), J (Hz)]: 8.43 (d, 1H, J = 8.8, CONHVal),
8.33 (dd, 1H, J = 4.8 and 2.0, H1), 8.16 (dd, 1H, J = 7.6 and 2.0, H3),
7.64−7.45 (m, 15H), 7.02 (dd, 1H, J = 7.6 and 4.8, H2), 6.71 (d, 1H,
J = 7.6, CONHiPro), 4.61 (dd, 1H, J = 8.8 and 4.4, CαH), 4.09 (m, 1H,
CiProH), 2.55 (m, 1H, CβH), 1.16 (d, 3H, J = 6.8, CiProH3), 1.15 (d,
3H, J = 6.8, CiProH3), 1.02 (d, 3H, J = 6.8, CχH3), 1.01 (d, 3H, J = 6.8,
CχH3). 31P NMR [CDCl3, 300 MHz, δ (ppm)]: 36.3. 13C NMR
[CDCl3, 300 MHz, δ (ppm), J (Hz)]: 170.2 (CONHiPro), 167.3
(CONHVal), 164.4 (C, Py), 149.1 (CH, C1), 139.0 (CH, C3), 134.3
(d, CH, J = 14.0, C5), 131.7 (d, CH, J = 2.5, C7), 131.1 (C, Py), 129.7
(d, C, J = 56.1, C4), 129.2 (d, CH, J = 11.5, C6), 118.9 (CH, C2), 59.7
(CαH), 41.6 (CiProH), 29.7 (CβH), 22.9 and 22.7 (CiProH3), 19.8 and
17.5 (CχH3). HRMS (ESI+) m/z: [MH]+ 754.1925 (calcd), 754.1077
(found); [M + AuPPh3]+ 1212.2. IR (cm−1): 3285 (br, NH), 1633
(s, CONH), 1571, 1524, and 1480 (w, Ar), 1100 and 1071 (w, CO),
746 and 710 (w, Ar). Anal. Calcd for C32H35AuN3O2PS: C, 51.00; H,
4.68; N, 5.58; S, 4.25. Found: C, 49.95; H, 4.58; N, 5.50; S, 4.09. TLC:
Rf = 0.2 (1:1 acetone/hexane). [α]D: −0.44 (c 1.0 g/mL, CHCl3).
[Au(SpyCOPheNHiPr)(PPh3)] (16). Yield: 0.353 g, 44.1%. 1H
NMR [CDCl3, 400 MHz, δ (ppm), J (Hz)]: 8.36 (d, 1H, J = 8.0,
CONHPhe), 8.28 (dd, 1H, J = 4.8 and 2.0, H1), 7.98 (dd, 1H, J = 8.0
and 2.0, H3), 7.61−7.46 (m, 15H), 7.28−7.16 (m, 5H), 6.95 (dd, 1H,
J = 8.0 and 4.8, H2), 6.54 (d, 1H, J = 7.6, CONHiPro), 4.93 (“ td”, 1H,
J = 8.2 and 6.7, CαH), 4.03 (“sexd”, 1H, J = 13.1 and 6.6, CiProH), 3.24
(d, 2H, J = 6.4, CβProH2), 1.07 (d, 3H, J = 6.4, CiProH3), 1.05 (d, 3H,
J = 6.4, CiProH3). 31P NMR [CDCl3, 400 MHz, δ (ppm)]: 36.0. 13C
NMR [CDCl3, 400 MHz, δ (ppm), J (Hz)]: 169.7 (CONHiPro), 166.9
(CONHPhe), 164.7 (C, Py), 148.7 (CH, C1), 138.4 (CH, C3), 137.1
(C, C8), 134.2 (d, CH, J = 14.0, C5), 131.6 (d, CH, J = 2.5, C7), 130.2
(C, Py), 129.5 (CH, R,C10), 129.1 (CH, J = 11.5, C6), 128.7 (d, C, J =
55.4, C4), 128.5 (CH, R, C9), 126.7 (CH, R, C11), 118.4 (CH, C2),
55.4 (CαH), 41.6 (CiProH), 37.9 (CβH2), 22.6 (CiProH3), 22.5 (CiProH3).
MS (ESI+) m/z: [MH]+ 802.2 (calcd), 802.1 (found); [M + AuPPh3]+
1260.1. IR (cm−1): 3270 (br, CONH), 1729 and 1635 (s, CONH),
1571, 1514, and 1480 (w, Ar), 1097 and 1017 (s, C−O), 745 and
709 (w, Ar). Anal. Calcd for C36H35AuN3O2PS: C, 53.93; H, 4.40; N,
5.24; S, 4.00. Found: C, 53.79; H, 4.50; N, 4.36; S, 3.81. TLC: Rf = 0.2
(1:1 acetone/hexane). [α]D: −9.06 (c 1.0 g/mL, CHCl3).
ASSOCIATED CONTENT
■
S
* Supporting Information
X-ray crystallographic file in CIF format, details of data collection
and structure refinement, and bond lengths and angles for
compounds 1 and 3. This material is available free of charge via
the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: gimeno@unizar.es.
[Au(SpyCOMetNHiPr)(PPh3)] (17). Yield: 0.345 g, 44%. 1H NMR
[CDCl3, 400 MHz, δ (ppm), J (Hz)]: 8.50 (d, 1H, J = 8.4, CONHMet),
8.33 (dd, 1H, J = 4.8 and 1.8, H1), 8.11 (dd, 1H, J = 7.6 and 1.8, H3),
Notes
The authors declare no competing financial interest.
G
dx.doi.org/10.1021/ic4003803 | Inorg. Chem. XXXX, XXX, XXX−XXX

Inorganic Chemistry
Article
(28) Nomiya, K.; Noguchi, R.; Shigeta, T.; Kondoh, Y.; Tsuda, K.;
Ohsawa, K.; Chikaraishi-Kasuga, N.; Oda, M. Bull. Chem. Soc. Jpn.
2000, 73, 1143.
(29) Fulmer, G. R.; Miller, A. J. M.; Sherden, N. H.; Gottlieb, H. E.;
Nudelman, A.; Stoltz, B. M.; Bercaw, J. E.; Goldberg, K. I.
Organometallics 2010, 29, 2176.
ACKNOWLEDGMENTS
■
́
The authors thank the Ministerio de Economia y Compet-
itividad-FEDER (Grants CTQ2010-20500-C02-01 and
CTQ2010-17436)) and DGA-FSE (E77 and E40) for financial
support. A.G. thanks to the CSIC for a JAE-predoc fellowship.
(30) Uson
(31) Sheldrick, G. M. SADABS, Program for absorption correction;
University of Gottingen: Gottingen, Germany, 1996.
(32) Multi-scans absorption correction with SCALE3 ABSPACK
scaling algorithm. CrysAlisPro, version 1.171.35.11; Agilent Technol-
ogies: Santa Clara, CA.
́
, R.; Laguna, A. Inorg. Synth. 1982, 21, 71.
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