Chiral AuI- and AuIII-Isothiourea Complexes: Synthesis, Characterization and Application

Article abstract of DOI:10.1002/chem.201804653

During an investigation into the potential union of Lewis basic isothiourea organocatalysis and gold catalysis, the formation of gold-isothiourea complexes was observed. These novel gold complexes were formed in high yield and were found to be air- and moisture stable. A series of neutral and cationic chiral gold(I) and gold(III) complexes bearing enantiopure isothiourea ligands was therefore synthesized and fully characterized. The steric and electronic properties of the isothiourea ligands was assessed through calculation of their percent buried volume and the synthesis and analysis of novel iridium(I)-isothiourea carbonyl complexes. The novel gold(I)- and gold(III)-isothiourea complexes have been applied in preliminary catalytic and biological studies, and display promising preliminary levels of catalytic activity and potency towards cancerous cell lines and clinically relevant enzymes.

Full text of DOI:10.1002/chem.201804653

A Journal of
Accepted Article
Title: Chiral Au(I)- and Au(III)-Isothiourea Complexes: Synthesis,
Characterization and Application
Authors: Danila Gasperini, Mark Greenhalgh, Rehan Imad, shehzaib
siddiqui, Anum malik, fizza Arshad, Muhammad Iqbal
choudhary, Abdullah Al-Majid, David Cordes, Alexandra
Slawin, Steven Nolan, and Andrew David Smith
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Chem. Eur. J. 10.1002/chem.201804653
Link to VoR: http://dx.doi.org/10.1002/chem.201804653
Supported by

10.1002/chem.201804653
Chemistry - A European Journal
FULL PAPER
Chiral Au(I)- and Au(III)-Isothiourea Complexes: Synthesis,
Characterization and Application
Danila Gasperini,[a] Mark D. Greenhalgh,[a] Rehan Imad,[b] Shezaib Siddiqui,[b] Anum Malik,[b] Fizza
Arshad,[b] Muhammad Iqbal Choudhary,[b,c] Abdullah M. A. Al-Majid,[e] David B. Cordes,[a] Alexandra M.
Z. Slawin,[a] Steven P. Nolan*[d,e], Andrew D. Smith*[a]
Dedication ((optional))
Abstract: During an investigation into the potential union of Lewis
basic isothiourea organocatalysis and gold catalysis, the formation of
gold-isothiourea complexes was observed. These novel gold
complexes were formed in high yield and were found to be air- and
moisture stable. A series of neutral and cationic chiral gold(I) and
gold(III) complexes bearing enantiopure isothiourea ligands was
therefore synthesized and fully characterized. The steric and
electronic properties of the isothiourea ligands was assessed
through calculation of their percent buried volume and the synthesis
and analysis of novel iridium(I)-isothiourea carbonyl complexes. The
novel gold(I)- and gold(III)-isothiourea complexes have been applied
in preliminary catalytic and biological studies, and display promising
preliminary levels of catalytic activity and potency towards cancerous
cell lines and clinically-relevant enzymes.
two catalysts must not engage exclusively in an interaction that
inhibits one or both of the catalytic manifolds. This is a particular
concern when combining a Lewis acidic transition metal and a
Lewis basic organocatalyst.
Based on the collective expertise of our research groups, we
envisaged the combination of isothiourea organocatalysis and
gold catalysis may be productive for the development of novel
enantioselective transformations.[2,3] Chiral isothioureas have
been widely-applied as Lewis base organocatalysts, capable of
promoting a diverse set of enantioselective transformations via
acyl isothiouronium, isothiouronium enolate and α,β-unsaturated
acyl isothiouronium intermediates.[2] Key to effective enantio-
induction in these processes is the proximity of an sp3-
hydribrized stereogenic carbon adjacent to the catalytically-
active Lewis basic sp2-hybridized nitrogen (Figure 1).[4]
1. Introduction
The concept of combining transition metal catalysis and
organocatalysis is attractive due to the potential for achieving
novel transformations impossible with either catalytic system
alone.[1] This approach offers many advantages, in particular for
the development of enantioselective transformations, where an
appropriate combination of chiral catalysts can be used to
achieve unprecedented levels of stereocontrol. Despite this
great promise, a number of significant challenges exist. The
reaction conditions must be compatible with both catalytic
manifolds and each catalyst must be able to selectively activate
a specific substrate and/or intermediate. Most significantly, the
Figure 1. Selected achiral and chiral Lewis basic isothiourea organocatalysts.
Recent developments in isothiourea catalysis have focused on
combining the nucleophilic isothiouronium enolate intermediate
with an electrophile that is catalytically-generated by a transition
metal (Scheme 1a).[5] Snaddon was first to report this successful
union by using a combination of BTM 2 and a palladium catalyst
for the enantioselective -allylation of aryl acetic acid esters
(Scheme 1b).[5a-f] Shortly afterwards, Hartwig reported
a
complementary iridium-catalyzed method to provide the related
branched products (Scheme 1c).[5h] Significantly, through
variation of the enantiomer of the isothiourea and iridium
catalysts applied, all four stereoisomers of the product could be
accessed with excellent diastereo- and enantioselectivity. More
recently, Gong, and Cao and Wu have exploited the merger of
isothiourea catalysis with copper catalysis, through the
generation of electrophilic copper-allenylidene intermediates[5i,j]
(Scheme 1d) or diaziridinone activation.[5k] In each example it
has been assumed that the Lewis base and transition metal-
catalyzed cycles operate independently, with no direct
interaction between the Lewis basic isothiourea and transition
metal required.
[a]
Dr D. Gasperini, Dr M. D. Greenhalgh, Dr D. B. Cordes, Prof. A. M.
Z. Slawin and Prof. A. D. Smith
EaStCHEM, School of Chemistry,
University of St Andrews, St Andrews, Fife, KY16 9ST, UK.
E-mail: ads10@st-andrews.ac.uk
[b]
R. Imad, S. Siddiqui, A. Malik, F. Arshad and Prof. M. I. Choudhary
H.E.J Research Institute of Chemistry, International Center for
Chemical and Biological Sciences,
University of Karachi, Karachi-75270, Pakistan.
Prof. M. I. Choudhary
[c]
[d]
[e]
Department of Biochemistry, Faculty of Science,
King Abdulaziz University, Jeddah-21412, Saudi Arabia.
Prof. A. A. M. Al-Majid and Prof. S. P. Nolan
Department of Chemistry and Center for Sustainable Chemistry,
King Saud University PO Box 2455, Riyadh, 11451, Saudi Arabia.
Prof. S. P. Nolan
Chemistry Department, College of Science,
Ghent University, Krijgslaan 281, 9000 Ghent, Belgium.
E-mail: Steven.Nolan@UGent.be
Supporting information for this article is given via a link at the end of
the document.
This article is protected by copyright. All rights reserved.

10.1002/chem.201804653
Chemistry - A European Journal
FULL PAPER
guanidine and isothiourea complexes 3 and 4 (Figure 2);[11,12]
however, these studies were mostly limited to the solution and
solid-state behavior of the complexes. Cronje also applied these
novel gold complexes in antitumoral and antimalarial screening,
however only minimal activity was observed.[12] Even more
scarce are reports on the synthesis of gold complexes bearing
chiral sp2-hybridized nitrogen-based ligands. Peters synthesized
and characterized dinuclear gold(I) and gold(II) ferrocenyl
oxazoline complexes 6,[13] however no applications of these
novel chiral complexes were disclosed.
Figure 2. Cationic and neutral gold(I)-guanidine and chiral dinuclear gold(I)-
oxazoline complexes.
Scheme 1. Recent examples of combining isothiourea and transition metal
catalysis.
Due to the wide variety of applications of gold complexes,[1,14]
where the nature of the ligands are pivotal for imparting stability
and functionality,[15] we pursued the synthesis of gold complexes
bearing novel isothiourea ligands. Beyond gold chemistry, the
use of isothiourea ligands for transition metal catalysts in
general has been somewhat overlooked. An example from
Doyle has demonstrated the addition of a chiral isothiourea to
the cobalt-catalyzed hydrofluorination of epoxides has a positive
effect.[16] It was proposed, based on spectroscopic studies, that
the isothiourea acts as a ligand to facilitate complex dimer
dissociation and enhance reactivity, however no isolated
complexes were reported. Considering this precedent, and the
current interest in combining isothiourea- and transition metal
catalysis, we believed that a fundamental study on the potential
for isothioureas to act as ligands for transition metals would be
of significant interest. Herein we report the synthesis,
characterization and preliminary applications of a range of novel
cationic and neutral chiral gold(I) and gold(III) isothiourea
complexes. The inherent steric and electronic properties of the
isothiourea ligands are assessed through computation and the
synthesis of novel iridium(I) isothiourea complexes, and their
catalytic and biological activities are evaluated in some
preliminary studies.
We reasoned that the ability of gold catalysts to activate alkenes
and alkynes could be exploited through combination with
isothiourea catalysis for the enantioselective -alkylation and -
vinylation of esters. The combination of gold with primary and
secondary amine catalysts has previously been explored,[6,7] but
to the best of our knowledge the use of tertiary amine catalysts
has not been reported. Initial studies into the potential of this
dual catalytic manifold found that despite screening a range of
gold complexes, solvents and reaction temperatures, neither
intra- nor intermolecular processes were successful (Scheme
2).[8] In each case only starting materials or hydrolysis products
were observed. Control studies identified rapid and irreversible
binding between the Lewis basic isothiourea and the Lewis
acidic gold catalyst. In contrast to previous methods using
primary and secondary amines, the addition of acid could not be
used to circumvent this deactivation pathway due to the
necessity of basic conditions for successful isothiouronium
enolate formation.
2. Results and Discussion
2.1. Cationic Heteroleptic Gold(I)-Isothiourea Complexes
2.1.1. Synthesis
The synthesis of cationic heteroleptic gold(I)-isothiourea
complexes was explored using easily-accessed gold(I) chloride
NHC and phosphine precursors. Halide abstraction from either
Scheme 2. Initial studies into the union of isothiourea and gold catalysis.
A survey of the literature at this point revealed that although gold
complexes containing simple alkylamine, nitrile, imine and
pyridine ligands have been explored,[9,10] the use of other neutral
sp2-hybridized nitrogen-based ligands has been less thoroughly
investigated. Schmidbaur and Cronje have reported the
synthesis and characterization of neutral and cationic gold(I)-
[Au(IPr)(Cl)] (IPr
= N,N'-bis(2,6-diisopropylphenyl)imidazol-2-
ylidene) 7 or [Au(PPh3)(Cl)] 8 using AgNTf2 or AgBF4, followed
by addition of an isothiourea led to rapid and quantitative
conversion to new gold(I)-isothiourea complexes 9–12 (Scheme
3). Recrystallization of the crude products from pentane afforded
pure, air- and moisture-stable microcrystalline gold(I) complexes.
This article is protected by copyright. All rights reserved.

10.1002/chem.201804653
Chemistry - A European Journal
FULL PAPER
Using this simple synthetic approach, a series of cationic gold(I)
complexes containing triflimide or tetrafluoroborate counterions
were synthesized in excellent yield (82–99%).
synthesized
from
gold(I)(NHC)(acetonyl)
complexes.[18a]
Reaction of these gold(I) triflimide complexes with isothioureas
(2S,3R)-3, (2R,3S)-3, (S)-2 or (R)-2 provided cationic gold(I)-
isothiourea complexes in uniformly excellent yields (96–99%)
(Scheme 5). Using this synthetic approach, the formation of (S)-
17·NTf2 and (2S,3R)-18·NTf2 bearing a chlorinated NHC ligand
could also be obtained in excellent yield. As a final alternative
approach, the heteroleptic cationic gold(I) acetonitrile complex,
[Au(IPr)(NCCH3)][BF4] 16,[20] was applied for the synthesis of
gold(I)-isothiourea BF4 adducts, (2S,3R)-9·BF4 and (S)-10·BF4,
which were both obtained in quantitative yield (Scheme 5).
Scheme 3. Synthesis of cationic heteroleptic gold(I)-isothiourea complexes
from gold(I) chloride precursors using silver-mediated halide abstraction. IPr =
N,N'-bis(2,6-diisopropylphenyl)imidazol-2-ylidene.
Due to the commonly-observed non-innocent role of silver in
gold catalysis,[17] alternative methods for the synthesis of these
complexes was investigated. We recently reported the silver-free
preparation of gold(I)(NHC)(acetonyl) complexes from
[Au(SMe2)(Cl)], an NHC·HCl salt and acetone in the presence of
potassium
carbonate.[18]
These
gold(I)(NHC)(acetonyl)
complexes proved excellent precursors to a range of gold
complexes. Applying this approach to the current study,
activation of [Au(IPr)(CH2C(O)CH3)] 13 using HBF4·OEt2,
followed by the addition of isothiourea (2S,3R)-3 gave (2S,3R)-
9·BF4 in quantitative yield (Scheme 4).
Scheme 5. Synthesis of cationic heteroleptic gold(I)-isothiourea complexes
from gold(I) triflimide complexes 14 and 15 and gold(I) acetonitrile BF4 adduct
16.
2.1.2. Characterization
Several distinguishing features of the cationic heteroleptic
1
gold(I)-isothiourea complexes were observed by H and 13C{1H}
NMR spectroscopy in CDCl3 (Table 1).[21] The C(2) proton of
HyperBTM 3 (N1-CHPh) was observed to undergo a significant
upfield shift (H ≈ −0.65 ppm) upon coordination to the NHC-
Au+ fragments of heteroleptic complexes 9 and 17 (entries 1–3).
In contrast, for [Au(PPh3)(HyperBTM)][NTf2] 11 the C(2) proton
of HyperBTM appeared in a more deshielded environment (H
= +0.20 ppm) (entry 4). The same trends were observed for the
analogous gold(I)-BTM complexes (entries 6–8), with the C(2)
proton of BTM 2 shielded when in combination with an NHC
ligand (H ≈ −0.30 ppm); and deshielded when combined with
PPh3 (H = +0.34 ppm). These variations in the effective
Scheme 4. Synthesis of cationic heteroleptic gold(I) complex (2S,3R)-9·BF4
from Au(I)-acetonyl complex 13.
The isolated Gagosz-type complexes 14 and 15,[19] which
contain a labile inner-sphere triflimide ligand, can also be
This article is protected by copyright. All rights reserved.

10.1002/chem.201804653
Chemistry - A European Journal
FULL PAPER
Table 1. Selected spectroscopic characterization of cationic heteroleptic gold(I) isothiourea complexes
entry
Compound
HyperBTM 3
H(N−CHPh) (ppm)
4.93
C(N=C−N) (ppm)
158.5
C(carbenic) (ppm)
(N=C−N) (cm−1
)
1
2
3
4
5
6
7
8
-
170.6
170.7
-
1627
[Au(IPr)(HyperBTM)][NTf2] 9
[Au(IPrCl)(HyperBTM)][NTf2] 17
[Au(PPh3)(HyperBTM)][NTf2] 11
BTM 2
4.31 (−0.62)[a]
4.27 (−0.66)[a]
5.13 (+0.20)[a]
5.67
167.9 (+9.4)[a]
168.1 (+9.6)[a]
166.8 (+8.3)[a]
166.6
1578 (−49)[a]
1576 (−51)[a]
1570 (−57)[a]
1593
-
[Au(IPr)(BTM)][NTf2] 10
[Au(IPrCl)(BTM)][NTf2] 18
[Au(PPh3)(BTM)][NTf2] 12
5.36 (−0.31)[b]
5.37 (−0.30)[b]
6.01 (+0.34)[b]
172.2 (+5.6)[b]
172.4 (+5.8)[b]
171.6 (+5.0)[b]
171.7
171.8
-
1560 (−33)[b]
1565 (−28)[b]
1570 (−23)[b]
[a] value in parentheses relative to free HyperBTM 3. [b] value in parentheses relative to free BTM 2.
shielding of the C(2) proton of the isothiourea ligand may reflect
differences in ion pairing between the heteroleptic complex and
the triflimide counterion influenced by the nature of the ancillary
ligand.[22] Another interesting feature observed by 1H NMR
spectroscopy was that the CH signals of the iso-propyl groups of
the C=N bond of the isothiouronium is weakened upon
complexation, and could be consistent with an increased
contribution from resonance bonding structures within the
isothiourea ligand. The complexes did not exhibit any
luminescence and therefore their photophysical properties were
not assessed further.
the NHC ligands in [Au(IPr)(HyperBTM)][NTf2]
9
and
[Au(IPrCl)(HyperBTM)][NTf2] 17 appear as two sets of septets
centred at ~2.35 ppm. This is consistent with a non-symmetrical
environment around the gold centre and indicate that rotation
around the Au–N is slow on the NMR timescale.
The structure of the heteroleptic complex (2R,3S)-9·NTf2 was
unambiguously established by single crystal X-ray diffraction
analysis (Figure 3).[24] The isothiourea binds as expected
through the nitrogen atom, with the complex adopting a near
linear geometry, with an N−Au−C angle of 176.2(5)°. The length
of the Au−N bond (2.053(11) Å) is slightly longer than those
reported for heteroleptic ylideneamine and acetonitrile
complexes ( = 0.02–0.04 Å),[12,9f,20] but similar in length to
heteroleptic tetramethylguanidine and pyridine complexes.[11,9f]
The Au−C distance of 1.979(13) Å is similar to that found in
heteroleptic gold(I)-NHC complexes bearing pyridine and
acetonitrile ligands, but shorter than in cationic homoleptic and
heteroleptic gold(I)-NHC complexes bearing ancillary NHC and
phosphine ligands. The N31−C32 and C32−N40 distances of
1.288(16) and 1.367(18) Å within the isothiourea ligand, reveal a
slight extension of the N31−C32 bond (+0.01 Å) and contraction
of the C32−N40 bond (−0.02 Å) relative to the free isothiourea.
This increase in N31−C32 bond length upon complexation is
consistent with the observed reduction in IR stretching frequency
of this fragment.
Analysis by 13C{1H} NMR spectroscopy revealed that the central
isothiouronium carbon (N=C–N) was shifted downfield in all
complexes, relative to the parent isothiourea (C = +5–10 ppm).
The magnitude of this downfield shift is consistent with those
previously reported for gold(I)-isothiourea complexes,[12] and
indicates that the positive charge is delocalized into the
isothiourea ligand, and at least partially centralized on the
isothiouronium carbon. The carbenic carbons of the NHC-Au-
isothiourea complexes 9, 10, 17, and 18 were observed at 171–
172 ppm (Table 1, entries 2,3,6,7). These carbenic carbon
chemical shifts are downfield relative to analogous cationic
homoleptic and heteroleptic gold(I)-NHC complexes bearing
ancillary NHC and phosphine ligands {e.g. [Au(IPr)2][BF4]: C
=
184.2 ppm; [Au(IPr)(PPh3)][BF4]:C = 188.2 ppm},[23] but upfield
relative to cationic heteroleptic complexes bearing other neutral
nitrogen-based ligands {e.g. [Au(IPr)(NCMe)][BF4]: C = 165.9
ppm;
[Au(IPr)(pyridine)][PF6]:
C
=
=
167.1
ppm;
[Au(NHC)(ylideneamine)][NO3]:C
165.6 ppm}.[9f,12] This
suggests that the gold centres in the heteroleptic complexes
bearing isothiourea ligands are more Lewis acidic than the
homoleptic and heteroleptic gold(I)-NHC complexes bearing
ancillary NHC and phosphine ligands; but less Lewis acidic than
those bearing alternative nitrogen-based ligands. This latter
observation could be rationalized by the high Lewis basicity of
isothioureas translating to their efficacy as σ-donating ligands.
Infrared spectroscopic analysis of the cationic heteroleptic
complexes revealed a lower stretching frequency of the N=C–N
unit in all complexes relative to the free isothiourea (Table 1).
This effect was most pronounced for complexes containing
HyperBTM (entries 1–4,  = −49−57 cm−1). This indicates that
This article is protected by copyright. All rights reserved.

10.1002/chem.201804653
Chemistry - A European Journal
FULL PAPER
H (N−CHPh) (ppm) 5.09 (+0.18)[b]
C (N=C−N) (ppm) 140.6 (−17.9)[b]
5.73 (+0.06)[c]
3.90 (+0.11)[d]
nd (−)[e]
140.0 (−26.6)[c]
1564 (−29)[c]
 (N=C−N) (cm−1
)
1575 (−52)[b]
1580 (−36)[d]
Scheme 6. Synthesis and selected spectroscopic characterization of neutral
gold(I)-isothiourea chloride complexes 20–22. [a] 16 h reaction time. [b] value
in parentheses relative to free HyperBTM 3. [c] value in parentheses relative to
free BTM 2. [d] value in parentheses relative to free DHPB 1. [e] not
determined.
(2R,3S)-9·NTf2
Au–N31
Au–C1
N31–C32
C32–N40
N31–Au–C1
2.053(11) Å
1.979(13) Å
1.288(16) Å
1.367(18) Å
176.2(5)°
of the isothiouronium units (N=C–N) were reduced in all
complexes relative to the free isothiourea ( = −39−52 cm−1).
This trend is consistent with that observed for the cationic
heteroleptic series, and may indicate increased contribution from
resonance bonding structures within the isothiourea ligand. It
may be pertinent to note that this apparent increased
delocalization in bonding does not necessarily correlate with an
increase in positive charge on the isothiourea ligand, as
evidenced by the shielding (rather than deshielding) of the
isothiouronium carbon. Once again, the complexes did not
exhibit luminescence and therefore their photophysical
properties were not assessed.
Colourless crystals of (2R,3S)-20, (±)-20, (S)-21 and 22 were
grown by slow diffusion of pentane or hexane into saturated
solutions in CH2Cl2, and their structures were unambiguously
determined by single crystal X-ray diffraction analysis (Figure
4).[25] All complexes are virtually linear along the N1–Au–
N31/N1–Au–Cl axes (177.3–179.5°), with Au–N bond lengths
within the range of 2.003–2.021 Å. These Au–N bond lengths
are considerably shorter than that observed for the heteroleptic
complex (2R,3S)-9·NTf2 (2.053 Å).
In complexes (2R,3S)-20 and (±)-20 bearing the HyperBTM
ligand, distortions in the nitrogen-carbon bond lengths were
consistent with the data obtained for the heteroleptic complex
(2R,3S)-9·NTf2. In both cases, slight extension of the
N1−C2/N31−C32 bond (+0.013 Å on average) and contraction of
the C2−N10/C32−N40 bond (−0.03 Å on average) relative to the
free isothiourea was observed. The enhanced extension of the
N1−C2/N31−C32 bond, relative to that observed for the
heteroleptic complex (2R,3S)-9·NTf2, is consistent with the lower
stretching frequency of the N=C−N fragment observed by IR
spectroscopy.
Figure 3. Thermal ellipsoid representation of (2R,3S)-9·NTf2 at 50%
probability. Hydrogen atoms omitted for clarity. Selected distances (Å) and
angles (°) given.
2.2. Neutral Gold(I)-Isothiourea Complexes
2.2.1. Synthesis
The synthesis of neutral gold(I)-isothiourea chloride complexes
was next targeted. Mixing [Au(SMe2)(Cl)] 19 and (S)-BTM (S)-2
in THF resulted in no conversion after 3 days at r.t.; however,
upon heating the same reaction mixture at 60 °C [Au((S)-
BTM)(Cl)] (S)-21 was obtained in quantitative yield within 1 h
(Scheme 6). The method was also applied to the synthesis of
gold(I) complexes bearing the (R)-enantiomer of BTM (R)-2;
racemic and both enantiomers of HyperBTM 3; and the achiral
isothiourea DHPB 1. The neutral gold(I) complexes bearing BTM
and HyperBTM ligands, 21 and 20, were obtained in quantitative
yield, while complex 22, bearing the achiral DHPB ligand, was
obtained in 85% yield. For the synthesis of 22 the use of K2CO3,
and an extended reaction time of 16 h, was required to obtain
high yields. All six complexes were obtained as bench-stable
solids. This is in contrast to previously-reported gold(I)-guanidine
chloride and bromide complexes, which were observed to
undergo rapid decomposition to give gold metal within a few
hours.[11]
2.2.2. Characterization
1H Spectroscopic analysis of the neutral gold(I)-isothiourea
complexes revealed the C(2) proton of all isothiourea ligands
had undergone
a small downfield shift relative to the
corresponding free isothiourea (Scheme 6, H = +0.06–0.18
ppm). A much more significant effect was observed by 13C{1H}
NMR spectroscopy, with substantial upfield shifts observed for
the isothiouronium carbons (N=C–N) relative to the free
isothioureas (C = −18–27 ppm). The IR stretching frequencies
This article is protected by copyright. All rights reserved.

10.1002/chem.201804653
Chemistry - A European Journal
FULL PAPER
version (±)-20 crystallizes in
a
heterochiral head-to-head
arrangement. In both cases, the isothiourea ligands are
effectively co-planar with one another. It is worth noting that all
four complexes appear similar by NMR spectroscopic analysis,
with only a single species observed in each case. This indicates
that the solid state structures may not be an accurate
representation of the complexes in the solution phase, and have
therefore been simply represented as gold(I)-isothiourea
chloride complexes in Scheme 6.
2.3. Gold(III)-Isothiourea Complexes
2.3.1. Synthesis
Having prepared and characterized a range of neutral and
cationic gold(I)-isothiourea complexes, the synthesis of gold(III)-
isothiourea analogues was investigated.[10j,26] The attempted
oxidation of (2S,3R)-20 and (S)-21 using Br2 or PhI(OAc)2
resulted in the formation of several species which could not be
fully analyzed or isolated. In contrast, the use of 1.2 equiv. of
PhICl2 led to the corresponding gold(III)-isothiourea trichloride
complexes (2S,3R)-23 and (S)-24 as purple and magenta solids
in quantitative yield (Scheme 7). Notably, oxidation of sulfur in
either isothiourea ligand, or the oxidative aromatization of BTM 2
was not observed. The same method was successfully applied
to the opposite enantiomers of 20 and 21, however the
attempted oxidation of 22 led to a complex mixture of products.
In addition, oxidation of the cationic heteroleptic complex (S)-
10·NTf2 gave a complex mixture of gold(I) and gold(III) species,
with [Au(IPr)Cl3] identified as the major product.[26b] To the best
of our knowledge, these complexes represent the first gold(III)
complexes bearing chiral nitrogen-based ligands.
(2R,3S)-20
(±)-20
Au–N1
Au–N31
2.011(8) Å
2.006(8) Å
1.297(14) Å
1.288(14) Å
1.358(13) Å
1.355(13) Å
177.3(4)°
2.003(5) Å
2.010(5) Å
1.280(6) Å
1.301(7) Å
1.358(8) Å
1.349(8) Å
178.69(15)°
N1–C2
N31–C32
C2–N10
C32–N40
N1–Au–N31
(S)-21
22
Au–N1
N1–C2
2.016(16)
Å
2.021(9) Å
1.31(2)
Å
1.316(15) Å
C2–N10
Au–Cl
1.34(2) Å
2.248(5) Å
179.5(4)°
1.341(13) Å
2.255(3) Å
178.7(3)°
H (N−CHPh) (ppm)
C (N=C−N) (ppm)
5.32 (+0.39)[a]
165.1 (+6.6)[a]
1574 (−53)[a]
6.36 (+0.69)[b]
169.7 (+3.1)[b]
1560 (−33)[b]
N1–Au–Cl
Figure 4. Thermal ellipsoid representations of (2R,3S)-20, (±)-20, (S)-21 and
22 at 50% probability. Hydrogen atoms omitted for clarity. Selected distances
(Å) and angles (°) given.
 (N=C−N) (cm−1
)
The X-ray crystal structures of the neutral gold(I)-isothiourea
complexes also reveal some striking differences. Whilst (S)-21
and 22 crystallize as linear gold(I)-isothiourea chloride
complexes, (2R,3S)-20 and (±)-20 crystallize in a cation-anion
Scheme 7. Synthesis and selected spectroscopic characterization of gold(III)-
isothiourea trichloride complexes. [a] value in parentheses relative to free
HyperBTM 4. [b] value in parentheses relative to free BTM 5.
2.3.2. Characterization
arrangement, consisting of
a cationic homoleptic gold(I)-
1H Spectroscopic analysis of the gold(III)-isothiourea trichloride
complexes 23 and 24 revealed that the C(2) proton of both
isothiourea ligands had undergone a large downfield shift
diisothiourea component and an anionic gold(I)-dichloride
counterion.[11] An interesting feature of the homoleptic
enantiopure complex (2R,3S)-20 is that the isothiourea ligands
are arranged in a head-to-tail configuration, whilst the racemic
relative to the corresponding free isothiourea (Scheme 7, H
=
This article is protected by copyright. All rights reserved.

10.1002/chem.201804653
Chemistry - A European Journal
FULL PAPER
+0.39–0.69 ppm). This downfield shift was significantly
enhanced relative to that observed for the corresponding gold(I)
chloride complexes 20 and 21, and is consistent with the
increased Lewis acidity of the d8 gold(III) centre. In both
complexes there is also a similar substantial downfield shift for
the isothiouronium carbons (N=C–N) relative to the gold(I)
chloride complexes (C = +25-30 ppm) (cf. Scheme 6). The IR
stretching frequencies of the isothiouronium units (N=C–N) were
also reduced in both complexes relative to the free isothiourea
( = −33−53 cm−1), and to a similar extent to that observed for
the corresponding neutral and cationic gold(I) complexes. Once
again, the complexes did not exhibit any luminescence and
therefore their photophysical properties were not assessed.
Colourless crystals of (2R,3S)-23 and (S)-24 were grown by
slow diffusion of pentane or hexane into saturated solutions in
CH2Cl2, and their structures were unambiguously determined by
single crystal X-ray diffraction analysis (Figure 5).[27] (2R,3S)-23
crystallized in the expected square planar configuration, in which
the Clcis–Au–Clcis plane was close to perpendicular to the plane
of the isothiourea ligand (77.1°). Extension of the N1−C2
bond(+0.015 Å) and contraction of the C2−N10 bond (−0.045 Å),
relative to the free isothiourea, was consistent with the trend
observed for the heteroleptic and neutral gold(I) complexes, and
with the reduction in stretching frequency of the N=C−N
fragment observed by IR spectroscopy. In contrast, (S)-24
crystallized in a cation-anion arrangement, similar to those
observed for (2R,3S)-20 and (±)-20. In this case however, the
cationic gold(III) diisothiourea dichloride complex and [AuCl4]−
counterion exist as a loose ion pair with no close Au−Au
contacts. As before, it is possible that the solid state structure
may not necessarily reflect the arrangement in solution.
2.4. Steric and Electronic Properties of Isothiourea Ligands
To provide an improved fundamental understanding of
isothiourea ligands in transition metal complexes, we next
appraised the steric and electronic parameters of the novel
isothiourea ligands used in this study. The steric properties of
the three isothiourea ligands was first investigated using the
percent buried volume (%VBur) metric.[28] Modelling the neutral
gold(I) complexes synthesized in this study, we obtained %VBur
values of 28.7% for (2R,3S)-20; 27.5% for (S)-21; and 25.1% for
22.[8] These steric parameters suggest that the isothiourea
ligands are quite small, with these %VBur values coinciding with
the lower range of %VBur values reported for common carbene
ligands (%VBur = 26–51%), and below the range reported for
phosphines (%VBur = 38–64%).[28]
The electronic effect of the isothiourea ligands was assessed
using the Tolman Electronic Parameter (TEP).[29] To determine
this parameter, the synthesis of iridium(I)-isothiourea carbonyl
complexes was undertaken. The reaction of [IrCl(cod)]2 25 with
either (2S,3R)-HyperBTM (2S,3R)-4 or DHPB 6 gave mono-
coordinated [IrCl{(2S,3R)-HyperBTM}(cod)] (2S,3R)-26 and
[IrCl(DHPB)(cod)] 27 as yellow solids in good to excellent
yield.[30] In contrast, the reaction of [IrCl(cod)]2 25 with BTM 5 led
to a complex inseparable mixture of products. Reaction of the
iridium(I) isothiourea complexes (2S,3R)-26 and 27 with 1 atm of
carbon monoxide gave [IrCl{(2S,3R)-HyperBTM}(CO)2] (2S,3R)-
28 and [IrCl(DHPB)(CO)2] 29 as off-white solids in quantitative
yield. (2S,3R)-26 and 27 and their carbonylated analogues,
(2S,3R)-28 and 29, were all produced as air- and bench-stable
complexes. It is interesting to note that in the methodology
reported by Hartwig on the union of isothiourea and iridium
catalysis, a pre-formed iridium phosphoramidite complex was
used.[5h] When in situ formation of the complex from [IrCl(cod)]2
25 and free ligand in the presence of the isothiourea catalyst
was attempted, only minimal product formation was achieved.
This result may be consistent with the effective binding we have
observed between isothioureas and iridium(I).
IR spectroscopic analysis was used to obtain the CO stretching
frequencies [(CO)] for the iridium(I)-isothiourea complexes,
(2S,3R)-28 and 29 (Scheme 8). Two variations of a linear
regression equation have been reported for the calculation of
TEPs of phosphine and NHC ligands bound to Ir(L)(Cl)(CO)2
complexes by Crabtree[31a] and Nolan,[31b] respectively. Applying
these two methods to the isothiourea ligands reported in this
study provide values of 2052.4 and 2048.1 cm−1 for HyperBTM 4,
and 2044.1 and 2038.3 cm−1 for DHPB 6. This analysis suggests
that these isothiourea ligands are significantly more electron-
donating than phosphine ligands (TEP of PCy3 = 2056.4 cm−1;
(2R,3S)-23
2.022(5) Å
-
(S)-24
Au–N1
Au–N21
N1–C2
1.988(11) Å
1.992(10) Å
1.323(18) Å
1.306(18) Å
1.321(18) Å
1.310(17) Å
-
1.294(7) Å
-
N21–C22
C2–N10
C22–N30
Au–Cltrans
Au–Clcis
1.341(8) Å
-
2.264(2) Å
2.276 Å[a]
2.275 Å[a]
N1–Au–
Cl3/N21
179.20(15)°
177.5(4)°
N1–Au–Clcis 87.73(15)/90.68(15)°
89.2(3)/92.5(3)°
Figure 5. Thermal ellipsoid representations of (2R,3S)-23 and (S)-24 at 50%
probability. Hydrogen atoms omitted for clarity. Selected distances (Å) and
angles (°) given. [a] Average value given.
This article is protected by copyright. All rights reserved.

10.1002/chem.201804653
Chemistry - A European Journal
FULL PAPER
PPh3 = 2068.9 cm−1) and similarly or more electron-donating
2.5. Preliminary Catalytic and Biological Studies
than NHC ligands (TEP of IAd = 2049.5 cm−1; IPr = 2051.5 cm−1). Having prepared and characterized a range of gold(I) and
This indicates that the isothiourea ligands used in this study are
highly efficient -donor ligands.
gold(III)-isothiourea complexes, preliminary investigations into
their catalytic and biological activities were performed.
2.5.1. Catalytic studies
Initial studies focused on using heteroleptic gold(I) complexes as
pre-catalysts for the hydroalkoxylation-Claisen rearrangement
using diphenylacetylene 30 and allyl alcohol 31 to give
homoallylic ketone 32.]33] Stoichiometric studies had
demonstrated that treatment of the heteroleptic gold(I)
complexes with HBF4·OEt2 would provide [Au(IPr)]+ following
release of the protonated isothiourea ligand. We speculated that
the protonated chiral isothiourea may be able to operate as a
hydrogen bond donor to catalyze the stereo-determining step of
the transformation. Activation of (2S,3R)-9·NTf2 (0.5 mol%)
using HBF4·OEt2 (0.5 mol%) provided homoallylic ketone 32 in
quantitative yield after 5 h at 120 °C, however the product was
obtained as a racemate (Table 5, entry 1). For context, the state-
of-the-art pre-catalyst, Au(IPrCl)(NTf2), provides 32 in quantitative
yield after 20 min under analogous conditions.[33] The reaction
temperature could be reduced to 60 °C using either (2S,3R)-
9·NTf2 or (2S,3R)-11·BF4 as pre-catalyst, providing 32 as a
racemate in 52–54% yield after 72 h (entries 2,3). In an attempt
to generate a chiral gold(I) catalyst in situ, activation of the
neutral gold(I) complex (2S,3R)-20 using sodium tetrakis[3,5-
(CO) (cm−1
)
1980.9; 2061.9
2021.4
1967.4; 2052.3
2009.8
bis(trifluoromethyl)phenyl]borate (NaBArF
) was investigated,
4
(CO)average
(cm−1)
however in this case no conversion of the starting materials was
observed (entry 4).
[a]
TEP (cm−1
TEP (cm−1
)
2052.4
2048.1
2044.1
2038.3
Table 2. Gold(I)-catalyzed hydroalkoxylation/Claisen rearrangement of
diphenylacetylene using allyl alcohol.
[b]
)
Scheme 8. Synthesis and characterization of iridium(I) isothiourea complexes.
[a] calculated using TEP = 0.722 × (CO)average + 593 cm−1 [31a]
[b] calculated
using TEP = 0.847 × (CO)average + 336 cm−1 [31b]
.
.
The structure of (2S,3R)-26 was unambiguously determined by
single crystal X-ray diffraction analysis (Figure 6).]32] The Ir−N1
distance of 2.104(8) Å, was longer than those observed for the
gold(I) and gold(III) complexes (1.99–2.05 Å). The complex
adopted the expected square planar configuration (N1−Ir−Cl =
87.0(2)°), with the isothiourea ligand in a perpendicular plane to
the Ir−Cl bond (C2−N1−Ir−Cl = 91.1(6)°).
entry
[Au]
Activator (mol%) T (°C)
t (h)
5
32 (%)[a]
1
2
3
4
(2S,3R)-9·NTf2
(2S,3R)-9·NTf2
(2S,3R)-11·BF4
(2S,3R)-20
HBF4·OEt2 (0.5)
HBF4·OEt2 (0.5)
HBF4·OEt2 (0.5)
NaBArF4 (1)
120
60
99
52
54
0
72
72
72
60
60
Reaction conditions: 30 (0.25 mmol), 31 (0.75 mmol), [Au] (0.5 mol%),
HBF4·OEt2 (0.5 mol%), solvent-free. [a] Isolated yield.
The in situ activation of neutral gold(I) pre-catalysts was further
investigated
for
the
gold-catalyzed
cyclization
of
silyloxyenynes.[34] Treatment of (2S,3R)-20 (4 mol%) with NaBF4
(8 mol%) at either −30 or 0 °C, did not promote cyclization of
TIPS-protected enol ether 33 (Table 3, entries 1,2), indicating
significantly lower activity than that previously reported using
Au(I)diphosphine complexes.[34] Activity was only achieved by
heating the reaction at reflux, to give cyclopentane 35 in 74%
yield after 48 h (entry 3). By switching the substrate to TBS-
protected enol ether 34, activation and subsequent cyclization
could be achieved at −30 °C to give cyclopentane 35 in 17%
(2S,3R)-26
Ir–N1
N1–C2
C2–N10
N1–Ir–Cl
C2–N1–Ir–Cl
2.104(8) Å
1.257(13) Å
1.365(13) Å
87.0(2)°
91.1(6)°
Figure 6. Thermal ellipsoid representation of (2S,3R)-26 at 50% probability.
Hydrogens omitted for clarity. Selected distances (Å) and angles (°) given.
This article is protected by copyright. All rights reserved.

10.1002/chem.201804653
Chemistry - A European Journal
FULL PAPER
yield (entry 4), however in both examples the product was
isolated as a racemate.
classes of the novel gold(I) and gold(III)-isothiourea complexes.
The isothiourea may either be used as a semi-labile ancillary
ligand or used as the sole ligand to provide stabilization of the
active gold catalyst. The isothioureas used in this study are
representative Lewis basic organocatalysts, and it is therefore
expected that rational modulation of ligand design will provide
isothioureas with improved properties as ligands. Such
modifications could include increasing the size of the
stereodirecting substituent on the isothiourea, and the
introduction of a second point of ligation to provide bidentate
ligand designs. This latter approach could be used for the
preparation of enantiopure digold complexes,37 or for the
development of enantioselective Au(III) catalysis.38 Beyond the
use of Au, complexation of these second generation ligands with
other transition metals may also provide catalysts, which could
be applied for a broad range of enantioselective transformations.
Table 3. Gold(I)-catalyzed cyclization of silyloxyenynes 33 and 34.
entry
Substrate
NaX
NaBF4
NaBF4
NaBF4
NaBArF
T (°C)
−30
0
t (h)
16
35 (%)[a]
1
2
3
4
33
33
33
34
0
0
16
84
48
76 (74)[b]
17[c]
2.5.2. Biological studies
−30
16
4
All three classes of the newly-synthesized cationic and neutral
gold(I) and gold(III)-isothiourea complexes were next examined
in some preliminary biological studies.[14a–c,39] Some significant
results are provided below, with full details available in the
Supporting Information.
Reaction conditions: silyloxyenyne 33 or 34 (0.04 mmol), (2S,3R)-20 (4 mol%),
NaX (8 mol%), DCE (0.02 M). [a] Conversions measured by 1H NMR
spectroscopy. [b] Isolated yield in parentheses. [c] Major product was
desilylated starting material.
Finally, the novel gold(III)-isothiourea complexes, (2S,3R)-23
and (S)-24, were applied as catalysts for the synthesis of allene
38 from propargylic alcohol 36 and mesitylene 37 (Table 4).[35]
Using (S)-24 (4 mol%), activated in situ with AgSbF6 (8 mol%),
allene 38 was obtained in high conversion after 20 min at 50 °C
Screening for antitumoral potency was performed against breast
cancer cell line MCF-7 and cervical cancer cell line HeLa, with
cytotoxicity evaluated using mouse fibroblast cell line 3T3 (up to
30 μM).[8] The most potent complexes were the heteroleptic
complexes bearing the BTM ligand: (R)-10·BF4, (S)-10·BF4 and
(S)-12·BF4, with IC50 values down to 0.3±0.01 μm (HeLa) and
0.6±0.2 μm (MCF-7) obtained. These activities are comparable
with those reported for the anti-cancer reference drug
Doxorubicin [IC50 (HeLa) = 0.3±0.02 μM; IC50 (MCF-7) =
0.92±0.01 μM], however all three complexes were also found to
be cytotoxic. The most promising compound tested was gold(III)
complex (S)-24, which displayed significant activity against both
HeLa and MCF-7 cell lines (IC50 values of 10±1 μM and 11±1 μM,
respectively), but did not exhibit cytotoxicity. In contrast, the
enantiomeric gold(III) complex (R)-24 displayed no activity
against HeLa or MCF-7.
(entry 1). Substituting AgSbF6 with NaBArF provided a boost in
4
activity, with allene 38 produced in quantitative yield after only
20 min at room temperature (entry 2). The use of (2S,3R)-23 (4
mol%), activated in situ with NaBArF (8 mol%), proved equally
4
effective (entry 3), however in all cases allene 38 was obtained
as a racemate. The addition of mesitylene 37 to propargylic
alcohol 36 was completely regioselective using both pre-
catalysts, with no formation of alkyne side-products arising from
C(1) addition of mesitylene.[35,36] Control reactions demonstrated
that an activator was required, but that sodium or silver salts
alone were not catalytically active.[8]
Table 4. Gold(III)-catalyzed synthesis of allene 38 from propargylic alcohol 36
and mesitylene 37.
Inhibition activities towards a range of enzymes including -
glucuronidase,[40]
carbonic
anhydrase,[41]
lipase,[42]
phosphodiesterase (PDE I),[43] tyrosinase[44] and dipeptidyl
peptidase were assessed next.[8] All complexes displayed
exceptionally-high -glucuronidase inhibition, with (S)-12·BF4
proving the most potent (IC50 = 0.11±0.001 μM). (S)-24, which is
not cytotoxic, was also
a highly potent inhibitor of -
entry
[Au]
(S)-24
Na or Ag salt
T (°C)
50
t (min) 38 (%)[a]
glucuronidase (IC50 = 0.19±0.09 μM) and compares favorably
with the commercially-available standard inhibitor, D-saccharic
acid 1,4-lactone (IC50 = 47±2 μM). Inhibition of the other
enzymes assayed was much less general. Three of the
heteroleptic gold(I) complexes [(R)-10·BF4, (R)-12·BF4, and (S)-
12·BF4] displayed potent activity against phosphodiesterase
(PDE I), however all other complexes were inactive. Four of the
neutral gold(I) complexes [(2R,2S)-20, (2S,2R)-20, (R)-21 and
(S)-21)] were potent for the inhibition of lipase, but only
moderate inhibition of carbonic anhydrase, tyrosinase and
dipeptidyl peptidase was observed with some of the complexes.
1
2
3
AgSbF6
20
20
20
83
(S)-24
NaBArF
r.t.
100
100
4
(2S,3R)-23
NaBArF
r.t.
4
Reaction conditions: 36 (0.1 mmol), 37 (0.7 mmol), [Au] (4 mol%), NaBArF4 or
AgSbF6 (8 mol%), DCE (0.07 M). [a] Conversions determined by 1H NMR
spectroscopy.
These preliminary studies have demonstrated
disparate transformations can be catalyzed by using all three
a range of
This article is protected by copyright. All rights reserved.

10.1002/chem.201804653
Chemistry - A European Journal
FULL PAPER
These preliminary studies demonstrate that gold-isothiourea
complexes display promising potency against cancer cell lines
and for the inhibition of enzymes. Further research is currently
underway to identify the mechanism of action in each example,
with this information expected to direct further modulation of
ligand design to provide more active and selective complexes.
Keywords: gold • coordination chemistry • N ligands •
homogeneous catalysis • bioinorganic chemistry
[1]
a) Z. Shao, H. Zhang, Chem. Soc. Rev., 2009, 38, 2745–2755; b) C.
Zhong, X. Shi, Eur. J. Org. Chem., 2010, 2999–3025; c) Z. Du, Z. Shao,
Chem. Soc. Rev., 2013, 42, 1337–1378; d) Y. Deng, S. Kumar, H.
Wang, Chem. Commun., 2014, 50, 4272–4284; e) S. Afewerki, A.
Córdova, Chem. Rev., 2016, 116, 13512–13570.
[2]
[3]
For reviews on isothiourea catalysis, see: a) J. Merad, J.-M. Pons, O.
Chuzel, C. Bressy, Eur. J. Org. Chem., 2016, 2016, 5589–5610; b) J. E.
Taylor, J. M. J. Williams, S. D. Bull, Chem. Soc. Rev., 2012, 41, 2109–
2121.
3. Conclusions
The attempted combination of gold catalysis and isothiouronium
enolate catalysis resulted in the formation of gold-isothiourea
complexes. These complexes proved to be air- and moisture-
stable for several months, and therefore their synthesis was
investigated in more detail. A range of gold(I), gold(III) and
iridium(I)-isothiourea complexes were synthesized in high yield
using chiral and achiral isothiourea ligands, with these novel
complexes characterized both in solution and in the solid state.
The chiral gold(III)-isothiourea complexes reported here
represent the first gold(III) species synthesized bearing chiral
nitrogen-based ligands. The inherent steric and electronic
properties of the isothiourea ligands have been analyzed using
the percent buried volume (%VBur) and Tolman Electronic
Parameter (TEP) descriptors. Based on this analysis, the
isothioureas used in this study are highly effective σ-donor
ligands. To the best of our knowledge this is the first appraisal of
steric and electronic parameters of isothioureas as ligands, and
thus should provide inspiration for the wider use of related
ligands for complexation with transition metals.
The gold(I) and gold(III) complexes were also applied as pre-
catalysts for several gold-catalyzed transformations. Promising
activities were found; however as the isothiourea ligands used
were based on those developed as organocatalysts, rational
modulation of ligand design will undoubtedly lead to further
improvements in the future. Finally, these complexes also
showed promising biological activity towards specific cancer cell
lines (MCF-7 and HeLa) and for the inhibition of clinically-
important enzymes (-glucuronidase and phosphodiesterase).
Elaboration of these preliminary studies is currently underway to
identify mechanisms of action, which will inform future work to
develop more highly active and selective complexes.[45]
For reviews on gold catalysis, see: a) D. J. Gorin, F. D. Toste, Nature,
2007, 446, 395–403; b) A. S. K. Hashmi, G. J. Hutchings, Angew.
Chem., Int. Ed., 2006, 45, 7896–7936; Angew. Chem., 2006, 118,
8064–8105; c) A. S. K. Hashmi, Chem. Rev., 2007, 107, 3180–3211; d)
Y. Wei, M. Shi, ACS Catal., 2016, 6, 2515–2524; e) M. Joost, A.
Amgoune, D. Bourissou, Angew. Chem. Int. Ed., 2015, 54, 15022–
15045; Angew. Chem., 2015, 127, 15234–15258.
[4]
a) V. B. Birman, X. Li, Org. Lett., 2006, 8, 1351–1354; b) X. Li, H. Jiang,
E. W. Uffman, L. Guo, Y. Zhang, X. Yang, V. B. Birman, J. Org. Chem.,
2012, 77, 1722–1737; c) C. Joannesse, C. P. Johnston, C. Concellón,
C. Simal, D. Philp, A. D. Smith, Angew. Chem. Int. Ed., 2009, 48,
8914–8918; Angew. Chem., 2009, 121, 9076–9080; d) C. Joannesse,
C. P. Johnston, L. C. Morrill, P. A. Woods, M. Kieffer, T. A. Nigst, H.
Mayr, T. Lebl, D. Philp, R. A. Bragg, A. D. Smith, Chem. Eur. J., 2012,
18, 2398–2408.
[5]
a) K. J. Schwarz, J. L. Amos, J. C. Klein, D. T. Do, T. N. Snaddon, J.
Am. Chem. Soc., 2016, 138, 5214–5217; b) J. W. B. Fyfe, O. M. Kabia,
C. M. Pearson, T. N. Snaddon, Tetrahedron, 2018, 74, 5383–5391; c) K.
J. Schwarz, C. M. Pearson, G. A. Cintron-Rosado, P. Liu, T. N.
Snaddon, Angew. Chem. Int. Ed., 2018, 57, 7800–7803; Angew. Chem.,
2018, 130, 7926–7929; d) W. R. Scaggs, T. N. Snaddon, Chem. Eur. J.,
2018, 24, 14378–14381; e) K. J. Schwarz, C. Yang, J. W. B. Fyfe, T. N.
Snaddon, Angew. Chem. Int. Ed., 2018, 57, 12102–12105; Angew.
Chem., 2018, 130, 12278–12281; f) L. Hutchings-Goetz, C. Yang, T. N.
Snaddon, ACS Catal., 2018, 8, 10537–10544; g) S. S. M. Spoehrle, T.
H. West, J. E. Taylor, A. M. Z. Slawin, A. D. Smith, J. Am. Chem. Soc.,
2017, 139, 11895–11902; h) X. Jiang, J. J. Beiger, J. F. Hartwig, J. Am.
Chem. Soc., 2017, 139, 87–90; i) J. Song, Z.-J. Zhang, L.-Z. Gong,
Angew. Chem., Int. Ed., 2017, 56, 5212–5216; Angew. Chem., 2017,
129, 5296–5300; j) X. Lu, L. Ge, C. Cheng, J. Chen, W. Cao, X. Wu,
Chem. Eur. J., 2017, 23, 7689–7693; k) J. Song, Z.-J. Zhang, S.-S.
Chen, T. Fan, L.-Z. Gong, J. Am. Chem. Soc., 2018, 140, 3177–3180.
C. C. J. Loh, D. Enders, Chem. Eur. J., 2012, 18, 10212–10255.
a) J. T. Binder, B. Crone, T. T. Haug, H. Menz, S. F. Kirsch, Org. Lett.,
2008, 10, 1025–1028; b) S. Belot, K. A. Vogt, C. Besnard, N. Krause, A.
Alexakis, Angew. Chem. Int. Ed., 2009, 48, 8923–8926; Angew. Chem.,
2009, 121, 9085–9088; c) T. Zweifel, D. Hollmann, B. Prüger, M.
Nielsen, K. A. Jørgensen, Tetrahedron: Asymmetry, 2010, 21, 1624–
1629; d) K. L. Jensen, P. T. Franke, C. Arróniz, S. Kobbelgaard, K. A.
Jørgensen, Chem. Eur. J., 2010, 16, 1750–1753; e) M. Chiarucci, M. di
Lillo, A. Romaniello, P. G. Cozzi, G. Cera, M. Bandini, Chem. Sci., 2012,
3, 2859–2863; f) Z. Wang, X. Li, Y. Huang, Angew. Chem. Int. Ed.,
2013, 52, 14219–14223; Angew. Chem., 2013, 125, 14469–14473; g) E.
Gómez-Bengoa, J. M. García, S. Jiménez, I. Lapuerta, A. Mielgo, J. M.
Odriozola, I. Otazo, J. Razkin, I. Urruzuno, S. Vera, M. Oiarbide, C.
Palomo, Chem. Sci., 2013, 4, 3198–3204; h) A. Ballesteros, P. Morán-
Poladura, J. M. González, Chem. Commun., 2016, 52, 2905–2908; i) J.
Fernández-Casado, R. Nelson, J. L. Mascareñas, F. López, Chem.
Commun., 2016, 52, 2909–2912.
[6]
[7]
Experimental Section
Detailed experimental procedures, characterization data, spectra and X-
ray crystallographic methods and data are available in the supporting
information.
Acknowledgements
ADS thanks the Royal Society for a Wolfson Research Merit
Award. We also thank the EPSRC UK National Mass
Spectrometry Facility at Swansea University. SPN thanks King
Abdullah University of Science and Technology (Award No.
OSR-2015-CCF-1974-03) and King Saud University for support.
[8]
[9]
See the Supporting Information for details.
a) B. P. Block, J. C. Bailar, J. Am. Chem. Soc., 1951, 73, 4722–4725;
b) G. Nardin, L. Randaccio, G. Annibale, G. Natile, B. Pitteri, J. Chem.
This article is protected by copyright. All rights reserved.

10.1002/chem.201804653
Chemistry - A European Journal
FULL PAPER
Soc., Dalton Trans., 1980, 220–223; c) E. Kimura, Y. Kurogi, T.
Takahashi, Inorg. Chem., 1991, 30, 4117–4121; d) H. Duan, S.
Sengupta, J. L. Petersen, N. G. Akhmedov, X. Shi, J. Am. Chem. Soc.,
2009, 131, 12100–12102; e) E. Herreo-Gómez, C. Nieto-Oberhuber, S.
López, J. Benet-Buchholz, A. M. Echavarren, Angew. Chem., Int. Ed.,
2006, 45, 5455–5459; Angew. Chem., 2006, 118, 5581–5585; f) P. de
Frémont, N. Marion, S. P. Nolan, J. Organomet. Chem., 2009, 694,
551–560; g) H. Duan, S. Sengupta, J. L. Petersen, N. G. Akhmedov, X.
Shi, J. Am. Chem. Soc., 2009, 131, 12100–12102; h) A. S. K. Hashmi,
C. Lothschütz, ChemCatChem, 2010, 2, 133–134.
Fischer, A. Laguna, M. C. Blanco, M. C. Gimeno, Angew. Chem. Int.
Ed., 2007, 46, 6184–6187; Angew. Chem., 2007, 119, 6297–6300.
[19] L. Ricard, F. Gagosz, Organometallics, 2007, 26, 4704–4707.
[20] P. de Frémont, E. D. Stevens, M. R. Fructos, M. Mar Díaz-Requejo, P.
J. Pérez, S. P. Nolan, Chem. Commun., 2006, 2045–2047.
−
[21] The identity of the counterion (NTf2 or BF4−) had minimal effect on the
spectroscopic data, and therefore only data for the complexes
containing NTf2− is presented in Table 1 and discussed in the text. Full
characterization data available in the Supporting Information.
[22] D. Zuccaccia, L. Belpassi, A. Macchioni, F. Tarantelli, Eur. J. Inorg.
Chem., 2013, 2013, 4121–4135.
[10] a) H.-N. Adams, J. Strähle, Z. Anorg. Allg. Chem., 1982, 485, 65–80; b)
H.-N. Adams, W. Hiller, J. Strähle, Z. Anorg. Allg. Chem., 1982, 485,
81–91; c) W. Conzelmann, W. Hiller, J. Strähle, G. M. Sheldrick, Z.
Anorg. Allg. Chem., 1984, 512, 169–176; d) J. Vicente, M.-T. Chicote, S.
Huertas, M. C. Ramírez de Arellano, P. G. Jones, Eur. J. Inorg. Chem.,
1998, 1998, 511–516; e) L. G. Kuz'mina, A. A. Bagatur'yants, A. V.
Churakov, J. A. K. Howard, Chem. Commun., 2001, 1394–1395; f) A. S.
K. Hashmi, J. P. Weyrauch, M. Rudolph, E. Kurpejović, Angew. Chem.
Int. Ed., 2004, 43, 6545–6547; Angew. Chem., 2004, 116, 6707–6709;
g) K. M.-C. Wong, L.-L. Hung, W. H. Lam, N. Zhu, V. W.-W. Yam, J. Am.
Chem. Soc., 2007, 129, 4350–4365; h) C. Khin, A. S. K. Hashmi, F.
Rominger, Eur. J. Inorg. Chem., 2010, 1063–1069; i) N. Savjani, D.-A.
Roşca, M. Schormann, M. Bochmann, Angew. Chem., Int. Ed., 2013,
52, 874–877; Angew. Chem., 2013, 125, 908–911; j) E. J. Fernández,
A. Laguna, J. M. López-de-Luzuriaga, M. Monge, M. Montiel, M. E.
Olmos, J. Pérez, M. Rodríguez-Castillo, Gold Bull., 2007, 40, 172–183;
k) S. Orbisaglia, B. Jacques, P. Braunstein, D. Hueber, P. Pale, A.
Blanc, P. de Frémont, Organometallics, 2013, 32, 4153–4164; l) D.-A.
Roşca, J. Fernandez-Cestau, J. Morris, J. A. Wright, M. Bochmann, Sci.
Adv., 2015, 1, e1500761; m) L. Huang, F. Rominger, M. Rudolph, A. S.
K. Hashmi, Chem. Commun., 2016, 52, 6435–6438; n) L. Huang, M.
Rudolph, F. Rominger, A. S. K. Hashmi, Angew. Chem. Int. Ed., 2016,
55, 4808–4813; Angew. Chem., 2016, 128, 4888–4893.
[23] S. Gaillard, P. Nun, A. M. Z. Slawin, S. P. Nolan, Organometallics, 2010,
29, 5402–5408.
[24] Crystallographic data for (2R,3S)-9·NTf2 (CCDC 1587865) is available
free of charge from the Cambridge Crystallographic Data Centre,
www.ccdc.cam.ac.uk/structures. (2R,3S)-9·NTf2 crystallized with two
ion pairs in the unit cell – only a single pair is shown in Figure 3 for
clarity.
[25] Crystallographic data for (2R,3S)-20 (CCDC 1587862), (±)-20 (CCDC
1587863), (S)-21 (CCDC 1587861) and 22 (CCDC 1587864) is
available free of charge from the Cambridge Crystallographic Data
Centre, www.ccdc.cam.ac.uk/structures.
[26] a) A. Collado, J. Bohnenberger, M.-J. Oliva-Madrid, P. Nun, D. B.
Cordes, A. M. Z. Slawin, S. P. Nolan, Eur. J. Inorg. Chem., 2016, 2016,
4111–4122; b) S. Gaillard, A. M. Z. Slawin, A. T. Bonura, E. D. Stevens,
S. P. Nolan, Organometallics, 2010, 29, 394–402; c) P. de Frémont, R.
Singh, E. D. Stevens, J. L. Petersen, S. P Nolan, Organometallics,
2007, 26, 1376–1385; d) M. Pažický, A. Loos, M. J. Ferreira, D. Serra,
N. Vinokurov, F. Rominger, C. Jäkel, A. S. K. Hashmi, M. Limbach,
Organometallics, 2010, 29, 4448–4458.
[27] Crystallographic data for (2R,3S)-23 (CCDC 1587867) and (S)-24
(CCDC 1587866) is available free of charge from the Cambridge
Crystallographic Data Centre, www.ccdc.cam.ac.uk/structures.
[28] a) H. Clavier,S. P. Nolan, Chem. Commun., 2010, 46, 841–861; b) A.
Poater, B. Cosenza, A. Correa, S. Giudice, F. Ragone, V. Scarano, L.
Cavallo, Eur. J. Inorg. Chem., 2009, 2009, 1759–1766; c) L. Falivene,
R. Credendino, A. Poater, A. Petta, L. Serra, R. Oliva, V. Scarano, L.
Cavallo, Organometallics, 2016, 35, 2286–2293.
[11] W. Schneider, A. Bauer, A. Schier, H. Schmidbaur, Chem. Ber., 1997,
130, 1417–1422.
[12] J. Coetzee, S. Cronje, L. Dobrzanska, H. G. Raubenheimer, G. Joone,
M. J. Nell, H. C. Hoppe, Dalton Trans., 2011, 40, 1471–1483.
[13] M. A. Garcia, W. Frey, M. R. Ringenberg, M. Schwilk, R. Peters, Chem.
Commun., 2015, 51, 16806–16809.
[29] a) C. A. Tolman, Chem. Rev., 1977, 77, 313–348; b) G. Ciancaleoni, N.
Scafuri, G. Bistoni, A. Macchioni, F. Tarantelli, D. Zuccaccia, L.
Belpassi, Inorg. Chem., 2014, 53, 9907–9916; c) D. Setiawan, R.
Kalescky, E. Kraka, D. Cremer, Inorg. Chem., 2016, 55, 2332–2344.
[30] The synthesis of nickel carbonyl complexes was originally investigated,
however the reaction of Ni(CO)4 with isothioureas 1–3 led to a complex
mixture of products.
[14] a) M. Bochmann, B. Bertrand, M. R. M. Williams, Chem. Eur. J., 2018,
24, 11840–11851; b) B. Bertrand, A. Casini, Dalton Trans., 2014, 43,
4209–4219; c) W. Liu, R. Gust, Chem. Soc. Rev., 2013, 42, 755–773;
d) I. Ott, Coord. Chem. Rev., 2009, 253, 1670–1681; e) V. W.-W. Yam,
K. M.-C. Wong, Chem. Commun., 2011, 47, 11579–11592; f) R. Visbal,
M. C. Gimeno, Chem. Soc. Rev., 2014, 43, 3551–3574; g) E. E.
Langdon-Jones, S. J. A. Pope, Chem. Commun., 2014, 50, 10343–
10354.
[31] a) A. R. Chianese, X. Li, M. C. Janzen, J. W. Faller, R. H. Crabtree,
Organometallics, 2003, 22, 1663–1667; b) R. A. Kelly III, H. Clavier, S.
Giudice, N. M. Scott, E. D. Stevens, J. Bordner, I. Samardjiev, C. D.
Hoff, L. Cavallo, S. P. Nolan, Organometallics, 2008, 27, 202–210.
[32] Crystallographic data for (2S,3R)-26 (CCDC 1587868) is available free
of charge from the Cambridge Crystallographic Data Centre,
www.ccdc.cam.ac.uk/structures.
[15] D. J. Gorin, B. D. Sherry, F. D. Toste, Chem. Rev., 2008, 108, 3351–
3378.
[16] a) J. A. Kalow, A. G. Doyle, J. Am. Chem. Soc., 2010, 132, 3268–3269;
b) J. A. Kalow, A. G. Doyle, J. Am. Chem. Soc., 2011, 133, 16001–
16012.
[17] a) D. Weber, M. R. Gagné, Org. Lett., 2009, 11, 4962–4965; b) D.
Wang, R. Cai, S. Sharma, J. Jirak, S. K. Thummanapelli, N. G.
Akhmedov, H. Zhang, X. Liu, J. L. Petersen, X. Shi, J. Am. Chem. Soc.,
2012, 134, 9012–9019; c) Z. Lu, J. Han, G. B. Hammond, B. Xu, Org.
Lett., 2015, 17, 4534–4537.
[33] A. Gómez-Suárez, D. Gasperini, S. V. C. Vummaleti, A. Poater, L.
Cavallo, S. P. Nolan, ACS Catal., 2014, 4, 2701–2705.
[34] J.-F. Brazeau, S. Zhang, I. Colomer, B. K. Corkey, F. D. Toste, J. Am.
Chem. Soc., 2012, 134, 2742–2749.
[35] C.-F. Xu, M. Xu, L.-Q. Yang, C.-Y. Li, J. Org. Chem., 2012, 77, 3010–
3016.
[18] a) D. Gasperini, A. Collado, A. Goméz-Suárez, D. B. Cordes, A. M. Z.
Slawin, S. P. Nolan, Chem. Eur. J., 2015, 21, 5403–5412. For previous
examples of Au(I) enolate complexes, see: b) Y. Ito, M. Inouye, M.
Suginome, M. Murakami, J. Organomet. Chem., 1988, 342, C41–C44;
c) M. Murakami, M. Inouye, M. Suginome, Y. Ito, Bull. Chem. Soc. Jpn.,
1988, 61, 3649–3652; d) L. G. Kuzmina, Koord. Khim., 1994, 20, 540–
546; e) F. Mohr, L. R. Falvello, M. Laguna, Eur. J. Inorg. Chem., 2006,
833–838; f) A. S. K. Hashmi, S. Schäfer, M. Wölfle, C. Diez Gil, P.
[36] a) M. Georgy, V. Boucard, J.-M. Campagne, J. Am. Chem. Soc., 2005,
127, 14180–14181; b) M. Georgy, V. Boucard, O. Debleds, C. D. Zotto,
J.-M. Campagne, Tetrahedron, 2009, 65, 1758–1766.
[37] a) Y.-M. Wang, A. D. Lackner, F. D. Toste, Acc. Chem. Res., 2014, 47,
889–901; b) W. Zei, F. D. Toste, Chem. Soc. Rev., 2016, 45, 4567–
4589.
This article is protected by copyright. All rights reserved.

10.1002/chem.201804653
Chemistry - A European Journal
FULL PAPER
[38] a) J. Rodriguez, D. Bourissou, Angew. Chem., Int. Ed., 2018, 57, 386–
388; Angew. Chem., 2018, 130, 392–394; b) P. T. Bohgan, F. D. Toste,
J. Am. Chem. Soc., 2017, 139, 11016–11019.
[39] a) A. M. Al-Majid, S. Yousuf, M. I. Choudhary, F. Nahra, S. P. Nolan,
Chem. Select, 2016, 1, 76–80; b) J. C. Lima, L. Rodriguez, Anticancer
Agents Med. Chem., 2011, 11, 921–928; c) L. Ortego, F. Cardoso, S.
Martins, M. F. Fillar, A. Laguna, M. Meireles, M. D. Vil-lamcampa, M. C.
Gimeno, J. Inorg. Biochem., 2014, 130, 32–37; d) F. K. Keter, I. A.
Guzei, M. Nell, W. E. Zyl, J. Darkwa, Inorg. Chem., 2014, 53, 2058–
2067; e) N. S. Jamaludin, Z. J. Goh, Y. K. Cheah, K. P. Ang, J. H. Sim,
C. H. Khoo, Z. A. Fairuz, S. N. Halim, S. W. Ng, H. L. Seng, E. R.
Tiekink, Eur. J. Med. Chem., 2013, 67, 127–141.
[40] Y.-T. Hsieh, K.-C. Chen, C.-M. Cheng, T.-L. Cheng, M.-H. Tao, S. R.
Roffler, PLoS One, 2015, 10, 1–23.
[41] H. Göçer, A. Akincioğlu, S. Göksu, İ. Gülçin, C. T. Supuran, J. Enzyme
Inhib. Med. Chem., 2015, 30, 316–320.
[42] M. L. Drent, Int. J. Obes. Relat. Metab. Disord. 1993, 17, 241–244.
[43] M. Kumazoe, S. Tsukamoto, C. Lesnick, N. E. Kay, K. Yamada, T. D.
Shanafelt, H. Tachibana, Br. J. Haematol., 2015, 168, 610–613.
[44] N. N. Bouzaiene, F. Chaabane, A. Sassi, L. Chekir-Ghedira, K. Ghedira,
Life Sci., 2016, 144, 80–85.
[45] The research data underpinning this publication can be found at
https://doi.org/10.17630/3ba256ef-6b22-4165-9c14-56b0357b036a.
This article is protected by copyright. All rights reserved.

10.1002/chem.201804653
Chemistry - A European Journal
FULL PAPER
Entry for the Table of Contents (Please choose one layout)
Layout 1:
FULL PAPER
Danila Gasperini,[a] Mark D.
An investigation into the union of
isothiourea organocatalysis and gold
catalysis led to the discovery of
bench-stable gold-isothiourea
complexes. A series of neutral and
cationic chiral gold(I) and gold(III)
complexes bearing enantiopure
isothiourea ligands have been
synthesized, with the steric and
electronic properties of the isothiourea
ligands also assessed. The novel
complexes have also been applied in
preliminary catalytic and biological
studies.
Greenhalgh,[a] Rehan Imad,[b] Shezaib
Siddiqui,[b] Anum Malik,[b] Fizza
Arshad,[b] Muhammad Iqbal
Choudhary,[b,c] Abdullah M. A. Al-Majid,[e]
David B. Cordes,[a] Alexandra M. Z.
Slawin,[a] Steven P. Nolan*[d,e], Andrew
D. Smith*[a]
Page No. – Page No.
Chiral Au(I)- and Au(III)-Isothiourea
Complexes: Synthesis,
Characterization and Application
Layout 2:
FULL PAPER
Author(s), Corresponding Author(s)*
((Insert TOC Graphic here; max. width: 11.5 cm; max. height: 2.5 cm))
Page No. – Page No.
Title
Text for Table of Contents
This article is protected by copyright. All rights reserved.