Design and synthesis of novel bis-thiazolone derivatives as micromolar CDC25 phosphatase inhibitors: Effect of dimerisation on phosphatase inhibition

Article abstract of DOI:10.1016/j.bmcl.2012.10.072

CDC25 phosphatases are involved in deregulated cell cycle progression and tumor development with poor prognosis. Among the most potent CDC25 inhibitors, quinonoid-based derivatives have been extensively studied. Dimerisation of heterocyclic quinones has led to IRC-083864, a bis-quinone compound with increased CDC25B inhibitory activity. Thirty-one bis-thiazolone derivatives were synthesized and assayed for CDC25 inhibitory activity. Most of the dimers displayed enhanced inhibitory activities with micromolar IC₅₀ values lower than that observed for each thiazolone scaffold separately. Moreover, most of these compounds were selective CDC25 inhibitors. Dimer 40 showed an IC ₅₀ value of 2.9 μM and could inhibit CDC25 activity without generating reactive oxygen species which is likely to occur with quinone-based inhibitors. Molecular docking studies suggested that the dimers could bind simultaneously to the active site and the inhibitor binding pocket.

Full text of DOI:10.1016/j.bmcl.2012.10.072

Bioorganic & Medicinal Chemistry Letters 22 (2012) 7345–7350
Contents lists available at SciVerse ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Design and synthesis of novel bis-thiazolone derivatives as micromolar
CDC25 phosphatase inhibitors: Effect of dimerisation on phosphatase inhibition
Manal Sarkis a, Diem Ngan Tran a, Stéphanie Kolb a, Maria A. Miteva b, Bruno O. Villoutreix b,
Christiane Garbay a, Emmanuelle Braud a,
⇑
a Laboratoire de Chimie et Biochimie Pharmacologiques et Toxicologiques, UMR 8601 CNRS, Université Paris Descartes, PRES Paris cité, 45 rue des Saints-Pères,
75270 Paris Cedex 06, France
b INSERM U973, Université Paris Diderot, 25 rue Hélène Brion, 75205 Paris Cedex 13, France
a r t i c l e i n f o
a b s t r a c t
Article history:
CDC25 phosphatases are involved in deregulated cell cycle progression and tumor development with
poor prognosis. Among the most potent CDC25 inhibitors, quinonoid-based derivatives have been exten-
sively studied. Dimerisation of heterocyclic quinones has led to IRC-083864, a bis-quinone compound
with increased CDC25B inhibitory activity. Thirty-one bis-thiazolone derivatives were synthesized and
assayed for CDC25 inhibitory activity. Most of the dimers displayed enhanced inhibitory activities with
micromolar IC50 values lower than that observed for each thiazolone scaffold separately. Moreover, most
Received 19 September 2012
Revised 12 October 2012
Accepted 15 October 2012
Available online 22 October 2012
Keywords:
Protein tyrosine phosphatases
CDC25
of these compounds were selective CDC25 inhibitors. Dimer 40 showed an IC50 value of 2.9 lM and could
inhibit CDC25 activity without generating reactive oxygen species which is likely to occur with quinone-
based inhibitors. Molecular docking studies suggested that the dimers could bind simultaneously to the
active site and the inhibitor binding pocket.
Bis-thiazolone derivatives
Ó 2012 Elsevier Ltd. All rights reserved.
Cell signaling is regulated by covalent and reversible phosphor-
ylation and dephosphorylation reactions which are controlled by
protein tyrosine kinases and phosphatases.1,2 These signaling path-
ways are responsible for essential cell events including growth,
differentiation, division or death. Thus, abnormal regulation of this
fine-tuned mechanism can lead to the development of human
diseases such as cancers.
Protein tyrosine phosphatases (PTPs), as their counterparts the
protein tyrosine kinases, are now considered as promising thera-
peutic targets.3,4 Their implication in numerous human diseases
has led to an intensive search for potent inhibitors.5 Among the
super family of PTPs, CDC25 phosphatases are dual-specificity
phosphatases which play a central role in cell cycle progression
and in the checkpoint response to DNA damage in normal cells.6,7
Three isoforms have been identified in human, namely CDC25A, B
and C.8–10 Up-regulation of CDC25A and B has been observed in a
wide variety of human cancers11,12 and CDC25 are also involved
in oncogenic transformation.13 Thus, isoforms A and B have been
identified as potential targets for cancer therapy. Consequently,
many efforts have been devoted to search for CDC25 inhibitors.
The most potent are quinonoid-based structures which have been
extensively studied.14 Dimerisation of heterocyclic quinones has
led to the bis-quinone IRC-083864 with increased potency which
is currently the most potent CDC25 inhibitor with IC50 values in
the nanomolar range (Fig. 1).15 In addition, it was demonstrated
to reduce the growth of prostatic and pancreatic human tumors
in mice with tumor xenografts. However, quinonoid-based inhibi-
tors are likely to induce toxicity, mostly by generating reactive
oxygen species during the redox cycling of quinone moieties.
Starting from in silico/in vitro screening experiments to identify
non quinonoid-based CDC25 inhibitors, we previously reported the
development of a series of thiazolopyrimidinone derivatives as
micromolar CDC25B inhibitors (Compound I, Fig. 1).16,17 These
compounds exhibited cytotoxic activity toward the human cancer
cell lines LNCaP (prostate) and MiaPaCa-2 (pancreatic adenocarci-
noma) and we also could show that they target CDC25B in cellular
assays. Moreover, analysis of the structure-activity relationship in
this series underlined the importance of the 4-hydroxybenzylid-
ene-thiazolone moiety for the phosphatase inhibitory activity.
Thus, we decided to evaluate the efficiency of compounds contain-
ing two 4-hydroxybenzylidene-thiazolone scaffolds toward
CDC25B activity (Fig. 1).
Herein, we describe the synthesis and the enzymatic evaluation
of bis-thiazolone derivatives as CDC25B inhibitors. To assess their
selectivity, we also examined their efficacy on two other protein
tyrosine phosphatases, namely PTP1B (Protein Tyrosine Phospha-
tase 1B) and VHR (Vaccinia virus H1 Related), the latter being a
dual-specificity phosphatase. In addition, molecular modeling
studies were performed to investigate the binding mode of these
new CDC25B inhibitors.
⇑
Corresponding author. Tel.: +33 142 864 085; fax: +33 142 864 082.
E-mail address: emmanuelle.braud@parisdescartes.fr (E. Braud).
0960-894X/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.bmcl.2012.10.072

7346
M. Sarkis et al. / Bioorg. Med. Chem. Lett. 22 (2012) 7345–7350
Fig. 1. CDC25 inhibitors and structures of the newly designed inhibitors.
Starting from the thiazolopyrimidinone I, we first decided to
simplify the chemical structure and conserved only the 4-hydrox-
ybenzylidene-thiazolone moiety. In first attempt, we thus
isomer. A Z-configuration of the exocyclic C@C bond was confirmed
by the chemical shift value of the methine proton, which was com-
parable to reported data for analogous derivatives.19,20
a
prepared thiazolones m1–m5 for a preliminary enzymatic evalua-
tion and bis-thiazolones 4–15 in order to investigate the nature of
the chain linking the two scaffolds (Scheme 1). Synthetic strategies
for the preparation of thiazolones are well documented in the
literature.18 Preparation of thiazolones m1–m5 and symmetrical
bis-thiazolones 4–15 and 27–35 was achieved according to re-
ported procedures for the preparation of 2-amino-5-benzylidene-
thiazol-4-one derivatives as described in Scheme 1. Rhodanine
was condensed with different aldehydes in the presence of
piperidine in ethanol to afford intermediates 1a, 1d and 1g–1l. Sub-
sequent activation of the thione function was realized via the for-
mation of the corresponding methyl thioethers 3a, 3d and 3g–3l.
An alternative route consisted first in the activation of the thione
function which led to the formation of compound 2 followed by
Knoevenagel condensation to give compounds 3b–3c and 3e–3f.
Thioethers 3a–3l were finally reacted with the selected amines or
di-amines in refluxing ethanol to afford the target compounds. All
intermediate and final compounds were obtained as a single
To complete the study concerning the nature of the linker, bis-
thiazolones 22–26 with a triazole-containing linker were prepared
using the well known (3+2) cyclo-addition developed by Huisgen
(Scheme 2). Azidothiazolones 17a and 17b were obtained by react-
ing azidoalkylamines 16a and 16b21 with 3a whereas alkyne deriv-
atives 21a–21c were synthesized in a similar way from the
propargylamine hydrochloride 20a and the alkynes 20b–20c pre-
pared using the method reported by Saito.22
Asymmetrical bis-thiazolones 40–44 were synthesized accord-
ing to the route described in Scheme 3. Key intermediate 38 was
obtained by introducing successively, the Boc-protected amino-
ethyl chain and the corresponding free amino ethyl chain on the
piperazine ring. Mono-thiazolone 39 was then prepared by react-
ing amino derivative 38 and 3a. The Boc group was cleaved using
TFA and the selected thiazolones 3b, 3g, 3i, 3k and 3l were intro-
duced in a similar way giving asymmetrical dimers 40–44.
All compounds were assayed for their inhibitory activity against
the recombinant fusion protein MBP-CDC25B, PTP1B and VHR
Scheme 1. Reagents and conditions: (a) RCHO, piperidine, EtOH, reflux, 12 h; (b) CH3I, DIPEA, EtOH, rt, 12 h; (c) CH3I, aq NaOH (0.5 M), rt, 24 h; (d) R1R2NH (1 equiv) or H2N-
linker-NH2 (0.5 eq), EtOH, reflux, 8 h.

M. Sarkis et al. / Bioorg. Med. Chem. Lett. 22 (2012) 7345–7350
7347
Scheme 2. Reagents and conditions: (a) NaN3, H2O, 80 °C, 5 h; (b) 3a, EtOH, reflux, 12 h; (c) MsCl, Et3N, Et2O, 0 °C, 3 h; (d) NaN3, DMF, 70 °C, 3 h; (e) PPh3, Et2O, 0 °C, 3 h; (f)
sodium ascorbate (1 equiv), CuSO4Á5H2O (10%), DMF/H2O, rt, 12 h.
Scheme 3. Reagents and conditions: (a) Boc2O, Et3N, MeOH, rt, 18 h; (b) piperazine (4 eq), K2CO3, NaI, acetone, reflux, 18 h; (c) 2-bromoethylammonium hydrobromide,
K2CO3, NaI, MeOH, reflux, 18 h; (d) 3a, EtOH, reflux, 16 h; (e) TFA, CH2Cl2, rt, 30 min; (f) 3b, 3g, 3i, 3k and 3l, MeOH, reflux, 16 h.
using fluorescein-3,6-diphosphate as the substrate.17 As can be
seen from the data reported in Table 1, mono-thiazolones m1–m5
were weakly active on CDC25B with percentage of phosphatase
activity inhibition between 10% and 45% at the concentration of
inhibitory activity with IC50 values between 2.5 and 13.9 lM. Sur-
prisingly, introduction of the aminated linker of IRC-083864 led to
a total loss of activity, the corresponding thiazolone 10 showing
only an inhibition of 30% of the phosphatase activity at the concen-
100
l
M. These compounds showed similar inhibitory activity to-
tration of 100 lM. A similar result was obtained for compound 11
ward PTP1B but appeared totally inactive on VHR at the same con-
centration. By contrast and as expected, most of the synthesized
bis-thiazolones 4–15 showed a large increase of the inhibitory
activity on CDC25B (Table 2). Compounds 4–9 containing an alkyl
chain with 4 to 9 carbon atoms displayed comparable CDC25B
with two oxygen atoms in the alkyl chain. Bis-thiazolones 12–15
with linkers containing aryl or alkyl rings were then prepared to
increase the rigidity. All dimers in this sub-series could inhibit
CDC25B activity with IC50 values in the micromolar range except
bis-thiazolone 15 bearing the longer chain which was inefficient
at the concentration of 100 lM. Thus, for this set of compounds,
the presence of hydrophobic linkers seems crucial for the inhibi-
tion of CDC25 enzymatic activity. As regards selectivity, all com-
pounds showed the same inhibitory profile on PTP1B, though
they generally appeared less active. Dimers 7 and 14 were the most
Table 1
Inhibitory activities of thiazolones m1–m5
Compd
–NR1R2
% of phosphatase inhibition at 100 l
Ma
CDC25B
PTP1B
VHR
selective with IC50 values of 3.4 and 2.2
30.6 and 46.0 M toward PTP1B. VHR was the less sensitive
enzyme with only bis-thiazolone 9 showing moderate inhibitory
activity (IC50 = 33 M). In conclusion, dimerisation of the
lM toward CDC25 versus
m1
m2
m3
m4
m5
–NHCH3
10%
20%
20%
10%
45%
32%
35%
35%
n.d.
46%
2%
0%
0%
n.d.
8%
l
–NH(CH2)3CH3
–NH(CH2)4CH3
–NH(CH2)3N(CH3)2
–NHBn
l
4-hydroxybenzylidene scaffold appeared here essential to increase
the inhibitory activity toward PTP1B and also, to a less extent,
toward VHR.
For the bis-thiazolones 22–26 with a triazole containing linker,
it could be noticed that the inhibitory activity increased with the
a
Inhibition of the activity of a maltose binding protein (MBP)-CDC25B, PTP1B
and VHR recombinant enzymes monitored with fluorescein 3,6-diphosphate (FDP).
The 50% inhibitory concentration mean values SEM were calculated from at least
two, usually three, independent experiments. n.d. not determined.

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M. Sarkis et al. / Bioorg. Med. Chem. Lett. 22 (2012) 7345–7350
Table 2
Inhibitory activities of bis-thiazolones 4–15
Compd
Linker
IC50 SEM (
lM) or % of phosphatase inhibition at 100
lM
CDC25B
PTP1B
VHR
4
5
6
7
8
9
10
11
Butyl
Pentyl
Hexyl
Heptyl
Octyl
nonyl
8.4 1.6
13.9 1.2
3.5 1.1
3.4 1.1
3.9 0.3
2.5 1.0
30%
28.4 7.9
20.6 6.9
12.4 0.9
30.6 11.3
11.6 5.9
6.2 2.6
n.d.
12%
75.8 6.7
26%
0%
29%
33.1 11.8
n.d.
n.d.
–(CH2)3N(CH3)(CH2)3
–(CH2)2O(CH2)2O(CH2)2–
12%
n.d.
12
13
14
6.6 0.3
9.0 1.0
30%
7.5 0.6
2.2 0.3
28%
9.1 0.8
46.0 2.4
n.d.
2%
N
N
N
N
13%
n.d.
15
n.d. not determined.
length of the side chains, triazole 26 being the most potent CDC25B
inhibitor with an IC50 value of 11.2 M (Table 3). The evaluation on
Table 4
Inhibitory activities of bis-thiazolones 27–35
l
PTP1B revealed that these sub-series was less active since triazoles
23–26 showed moderate inhibitory activity at the concentration of
Compd
R
IC50 SEM (
l
M) or% of phosphatase
inhibition at 100
lM
50 lM with percentage of inhibition between 20% and 50%. By con-
trast with the previous set of dimers, VHR was more sensitive to
this set of bis-thiazolones with percentage of inhibition ranking
from 38 to 55% at the concentration of 100 lM.
From these results, new symmetrical dimers 27–35 were pre-
pared to investigate the importance of the 4-hydroxyphenyl moi-
ety. Since compound 7 appeared to be one of the most selective
CDC25 inhibitor, the heptyl chain was chosen to link both thiazo-
lone scaffolds. The enzymatic results are gathered in Table 4. Intro-
duction of 4-hydroxyphenyl derivatives led to dimers 27–29 with
CDC25B
PTP1B
VHR
27
⁄
1.38 0.1
49%
24.2 4.5
100%
31%a
H3CO
HO
28
29
2%
22%
38%
H3CO
HO
2.7 0.3
23.4 8.6
HO
micromolar IC50 values (27: IC50 = 1.38
except dimer 28 which was weakly active at the concentration of
100 M. Thus, the introduction of two bromine atoms or a hydro-
lM and 29, IC50 = 2.7 lM),
30
31
21.0 6.5
11.9 1.5
41.3 13.1
26.9 4.0
28%
l
xyl group at position 3 of the phenyl ring retained the level of
inhibitory activity whereas the presence of two methoxy donating
groups was detrimental for potent CDC25 inhibition. Suppressing
the 4-hydroxy substituent gave dimer 30 with an IC50 value of
12.0 1.4
HO2C
O
32
13.8 0.9
30%
27%
21 lM, suggesting that the hydroxy group is not crucial for CDC25B
O
inhibitory activity. Replacing the hydroxyl group by the 2-carboxy-
vinyl moiety led to dimer 31 which could inhibit the activity of the
three phosphatases. The effects of bicyclic substituents were then
explored by introducing a benzodioxolane moiety which led to
33
34
45%
n.d.
51%
n.d.
34%
the active compound 32 (IC50 = 13.8
derivative 33 was less active with only 45% of inhibition of CDC25B
activity at the concentration of 100 M. Finally, the presence of the
lM). By contrast, the naphthyl
7.7 1.9
O
l
35
2.4 0.1
50%
30%
vinyl or the 5-phenylfuryl moieties gave compounds 34 and 35
with micromolar inhibitory activities. As for symmetrical 4-
a
Tested at the concentration of 10 lM. n.d. not determined.
Table 3
Inhibitory activities of bis-thiazolones 22–26
hydroxyphenyl derivatives, this set of compounds was less effi-
cient toward PTP1B, bis-thiazolones 32, 34 and 35 containing bicy-
clic substituents or vinyl groups showing an important loss of
activity. Similarly to the previous case, symmetric dimers were
not able to inhibit VHR activity except bis-thiazolones 27 (31% of
inhibition at 10 lM) and 31 (IC50 = 12.0 lM). Finally, compounds
34 and 35 are rather selective inhibitors of CDC25B.
Asymmetrical bis-thiazolone derivatives 40–44 containing
one 4-hydroxyphenyl moiety were also tested for their anti-
phosphatase activity (Table 5). Introduction of previously evaluated
Compd
m
n
IC50 SEM (lM) or% of phosphatase inhibition at 100 lM
CDC25B
PTP1Ba
VHR
22
23
24
25
26
2
2
3
3
3
1
3
1
2
3
0%
n.d.
35%
25%
20%
50%
n.d.
48%
55%
38%
43%
48.4 2.9
40.1 5.1
20.6 1.3
11.2 1.3
a
The percentages of inhibition were determined at the concentration of 50
n.d. not determined.
lM.

M. Sarkis et al. / Bioorg. Med. Chem. Lett. 22 (2012) 7345–7350
7349
Table 5
change the conformations, for example, R544 and R482, thus mod-
ifications might be possible in the binding mode. Further, this flex-
ibility may permit the CDC25 binding zone to adopt different
conformations that enable dimer molecules with different linker
size to act as potent inhibitors. The several polar side chains pres-
ent in both active site and inhibitor binding site and the hydropho-
bic patch in the cleft between R544 and R482 suggest that the
predicted binding mode is relevant and other similar dimer mole-
cules could bind in both active and inhibitor binding sites.
The effects of increasing concentrations of dithiothreitol (DTT)
on the inhibitory activity of the most potent inhibitors 7 and 27
were then explored to investigate their mechanism of action. En-
zyme assays were performed by replacing the DTT concentration
of 1 mM, normally used under our conditions, by 10 and 20 mM.
Results are reported in Table 6. Menadione which is an irreversible
quinonoid-based CDC25 inhibitor was also evaluated.25 As previ-
ously reported by us for menadione,17 an increase in DTT concen-
tration correlated with a decrease in the inhibitory activity. Indeed,
menadione could inhibit CDC25 activity with only 14% with a
concentration of 20 mM of DTT which is consistent with reactive
oxygen species (ROS) generation in vitro. To a less extent, an in-
crease of the IC50 values could also be observed for compound 7
which is thus likely to inhibit CDC25 by oxidizing the catalytic cys-
teine. By contrast, the inhibitory activity of bis-thiazolone 27 was
not affected by various concentrations in reducing agent. Thus,
compounds 7 and 27 show distinct redox profiles, suggesting dif-
ferent mechanisms of action for the two inhibitors.
Inhibitory activities of bis-thiazolones 40–44
Compd
R
IC50 SEM (lM) or% of phosphatase
inhibition at 100
lM
CDC25B
2.9 0.3
PTP1B
VHR
26%
Br
Br
100%
33%a
HO
40
41
O
4.4 0.5
19%
29%
O
42
43
57.3 14.4
8.5 2.1
13%
39%
23%
32%
O
N
44
2.9 0.8
18%
25%
HN
a
Tested at the concentration of 10 lM.
substituents such as 3,5-dibromo-4-hydroxyphenyl or benzodiox-
olyl groups led to compounds 40 and 41 with micromolar IC50
values whereas bis-thiazolone 42 showed a weaker affinity with
In summary, we designed and synthesized new series of sym-
metrical and asymmetrical bis-thiazolone derivatives. Enzymatic
evaluation revealed that dimerisation of the thiazolone scaffold en-
hanced the potency of the inhibitors. Indeed, most of the dimers
displayed micromolar IC50 values while the corresponding mono-
an IC50 value of 57.3
l
M. Other substituents such as furyl (43:
IC50 = 8.5 M) or indazolyl (44: IC50 = 2.9
l
lM) could also be well
tolerated. Replacement of one 4-hydroxyphenyl moiety abolished
PTP1B inhibition and led to compounds which are selective
inhibitors of CDC25B, except in the case of bis-thiazolone 40.
The binding mode of bis-thiazolone 7 was further investigated
by molecular docking using the CDC25B X-ray structure (PDB code:
1CWT).23 Among several low-energy poses generated by docking
with Surflex-Dock,24 the selected, after 5 visual analysis, pose
(Fig. 2A) suggests that this inhibitor interacts favourably with both
catalytic and inhibitor binding sites, which is in agreement with
our previously performed docking simulations.17 The docked pose
suggests that the 4-hydroxybenzylidene-thiazolone moieties
interact with the active site and the inhibitor binding pocket
(swimming-pool). The 4-hydroxyphenyl moieties can form hydro-
gen bonds with R497 and R482 in the active site and the inhibitor
binding site, respectively. The two C@O groups can be involved in
hydrogen bonds with Y428 and R548, respectively. The linker is
placed in the cleft between the residues R482 and R544 interacting
mers revealed weakly active at the concentration of 100 lM. This
effect could also be observed on protein tyrosine phosphatase
PTP1B with symmetrical bis-thiazolones, asymmetrical com-
pounds being inactive. Finally, the dual-specificity phosphatase
VHR was the less sensitive protein. We also could show that the
most effective CDC25 inhibitor could inhibit phosphatase activity
without generating ROS in vitro which is essential for further
development of CDC25 inhibitors. The performed docking analysis
suggested that dimer compounds can bind simultaneously in the
Table 6
Effect of various concentrations of DTT on the in vitro inhibition of CDC25B
Compd
IC50 SEM(lM) or% of CDC25 phosphatase inhibition at 100 lM
1 mM DTT
10 mM DTT
20 mM DTT
with the hydrophobic patch formed by the b- and c-CH2 groups of
Menadione
7
27
2.2 0.6
3.4 1.1
1.38 0.1
27%
16.5 8.0
3.1 2.4
14%
20.0 9.0
3.2 2.0
R479 and the residues Y428, and F543. The binding site of CDC25 is
shown in Figure 2B. The analysis of several X-ray structures of the
catalytic domain of CDC25B showed that several side chains
B
A
E448899
R448822
C447733
F447755
E448866
R554444
W555500
Figure 2. (A) Proposed binding modes for bis-thiazolone 7. The active site is circled with green dotted line and the inhibitor binding pocket is in orange. (B) The catalytic and
inhibitor binding sites are coloured by atom type (PDB code: 1CWT).

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M. Sarkis et al. / Bioorg. Med. Chem. Lett. 22 (2012) 7345–7350
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active and inhibitor binding sites that is in line with the observed
increased inhibitor potency for the synthesized dimer molecules.
All together, these findings suggest that dimerisation of known
CDC25 inhibitors could be a valuable approach in the search for
inhibitors with increased potency.
Acknowledgments
We thank Pr B. Ducommun of the University of Toulouse for
kindly providing the recombinant fusion MBP-CDC25B protein.
16. Montes, M.; Braud, E.; Miteva, M. A.; Goddard, M. L.; Mondesert, O.; Kolb, S.;
Brun, M. P.; Ducommun, B.; Garbay, C.; Villoutreix, B. O. J. Chem. Inf. Model.
2008, 48, 157.
Supplementary data
17. Kolb, S.; Mondesert, O.; Goddard, M. L.; Jullien, D.; Villoutreix, B. O.; Garbay, C.;
Braud, E. ChemMedChem 2009, 4, 633.
18. Pulici, M.; Quartieri, F. Tetrahedron Lett. 2005, 46, 2387.
19. Bourahla, K.; Dercour, A.; Rahmouni, M.; Carreaux, F.; Bazureau, J. P.
Tetrahedron Lett. 2007, 48, 5785.
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.bmcl.2012.10.072.
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