Approach to ferrocenyl-podophyllotoxin analogs and their evaluation as anti-tumor agents

Article abstract of DOI:10.1016/j.jorganchem.2017.02.005

Podophyllotoxin is a natural product endowed of a high antimitotic activity and a high affinity for tubulin. Its action results in the cessation of cell division, inducing cell death. However, its high toxicity restrains its use as drug. To overcome this drawback, several chemical modifications of the native podophyllotoxin have been made. However, to date, no reports have so far been directed toward incorporation of a metallocene moiety. The search for new organometallic drugs is a central field in drug discovery, including the domain of cancer therapy. In particular, metallocenyl moieties are known to increase or decrease, depending on the degree of conjugation in the organometallic motif, the selectivity of drugs toward cancer cells. The conjugate organometallic compound reduces the damage of healthy tissues, yet permitting the selective desired antimitotic and cytotoxic effects of the active principle. We report here the synthesis of ferrocene-containing podophyllotoxin analogs and preliminary antiproliferative tests.

Full text of DOI:10.1016/j.jorganchem.2017.02.005

Journal of Organometallic Chemistry xxx (2017) 1e8
Contents lists available at ScienceDirect
Journal of Organometallic Chemistry
journal homepage: www.elsevier.com/locate/jorganchem
Approach to ferrocenyl-podophyllotoxin analogs and their evaluation
as anti-tumor agents
*
ꢀ
ꢁ
Matthieu Beauperin, Dilan Polat, Fares Roudesly, Siden Top, Anne Vessieres, Julie Oble ,
**
***
ꢀ
Gerard Jaouen , Giovanni Poli
ꢀ
ꢀ
Sorbonne Universites, UPMC Univ Paris 06, CNRS, Institut Parisien de Chimie Moleculaire (IPCM), UMR 8232, 4, place Jussieu, 75005 Paris, France
a r t i c l e i n f o
a b s t r a c t
Article history:
Podophyllotoxin is a natural product endowed of a high antimitotic activity and a high affinity for
tubulin. Its action results in the cessation of cell division, inducing cell death. However, its high toxicity
restrains its use as drug. To overcome this drawback, several chemical modifications of the native
podophyllotoxin have been made. However, to date, no reports have so far been directed toward
incorporation of a metallocene moiety. The search for new organometallic drugs is a central field in drug
discovery, including the domain of cancer therapy. In particular, metallocenyl moieties are known to
increase or decrease, depending on the degree of conjugation in the organometallic motif, the selectivity
of drugs toward cancer cells. The conjugate organometallic compound reduces the damage of healthy
tissues, yet permitting the selective desired antimitotic and cytotoxic effects of the active principle. We
report here the synthesis of ferrocene-containing podophyllotoxin analogs and preliminary anti-
proliferative tests.
Received 5 December 2016
Received in revised form
6 February 2017
Accepted 6 February 2017
Available online xxx
Keywords:
Antitumor agent
Bioorganometallic chemistry
Ferrocene
Multi-step synthesis
Palladium
© 2017 Elsevier B.V. All rights reserved.
Podophyllotoxin
1. Introduction
emerged, and are now widely used drugs for chemotherapies in
lung cancer, lymphomas and genital tumors [6]. Intriguingly
In the family of cyclolignans, podophyllotoxin (PPT), a penta-
cyclic aryl-tetralin lignan isolated from the roots and rhizomes of
the American Mayapple (Podophyllum Peltatum) [1] (Fig. 1, left), has
attracted much attention as it has shown various biological activ-
ities among which an interesting antiproliferative effect. This
antineoplastic activity arises from inhibition of tubulin polymeri-
zation [2], a cytosolic protein required for the formation of the
mitotic spindle. However, PPT exhibits a high toxicity and serious
side effects like nausea, diarrhea, vomiting and damage to healthy
tissue. Accordingly, its use is currently restricted to local treatments
[3]. To overcome these drawbacks, several structure modification of
podophyllotoxin have been performed on rings C (particularly the
C-4 position), D and E, in view of obtaining more efficient and less
toxic anticancer agents [4]. In particular, the two semi-synthetic
derivatives, etoposide and teniposide [5] (Fig. 1, right), have
enough, unlike their parent compound, these derivatives are not
tubulin inhibitors, acting on topoisomerase II. Structure activity
relationship (SAR) studies suggest that topoisomerase II inhibition
activity is (among other requisite features) associated to the pres-
ence of a free 4’-hydroxy group [3a]. However, etoposide is asso-
ciated with some issues such as drug resistance and poor
bioavailability. Furthermore, picropodophyllin (PPP) (Fig. 1, left),
the C-2 epimer of PPT, although showing no activity against either
tubulin or topoisomerase, displays inhibitory activity against
tyrosine phosphorylation of Insulin-like Growth Factor 1 receptor
(IGF-1R) [7], which plays a crucial role in the transformation,
growth, and survival of malignant cells.
Due to the severe toxic effects of podophyllotoxin and its de-
rivatives, the discovery of more potent and/or less toxic analogs of
this family is highly desirable. Most of the PPT analogs have been
prepared from the native molecule by functionalization of the 4-
hydroxy group [8]. As a consequence, modifications of ring E have
been to date only scarcely explored [9]. A modern strategy towards
the modulation of biologically active products consists in the
incorporation of an organometallic motif into the drug [10,11].
Although organometallic compounds where used in therapy as
early as the beginning of the 20th century, this research field
* Corresponding author.
** Corresponding author.
*** Corresponding author.
E-mail addresses: julie.oble@upmc.fr (J. Oble), gerard.jaouen@chimie-paristech.
fr (G. Jaouen), giovanni.poli@upmc.fr (G. Poli).
http://dx.doi.org/10.1016/j.jorganchem.2017.02.005
0022-328X/© 2017 Elsevier B.V. All rights reserved.
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2
Scheme 1. Esterification of native PPT with ferrocenoyl chloride.
Fig. 1. Podophyllotoxin, picropophyllin, etoposide and teniposide structures.
multistep synthesis. Accordingly, we decided to exploit a method
we developed a few years ago [17] that gives access to the -oxo-
ester key fragment A [18] (Scheme 2). This latter can be reached
from the allylated -dicarbonyl B via an intramolecular 6-exo
Mizoroki-Heck coupling followed by alkene cleavage. B can result
from a -dicarbonyl derivative by allylation and alkylation with a
remained unexplored until 1996, when ferrocifen, a ferrocenyl
analog of tamoxifen, was reported, showing a high antiproliferative
effect against two breast cancer cell lines: MCF-7 and MDA-MB-231
[12]. The mechanism of action of ferrocifen on MCF-7 cells seems to
be partly analogous to that of tamoxifen, i.e. an antagonist effect on
g
b
b
a
-type oestrogen receptors (ERa). Yet, MDA-MB-231 cells, lacking
ferrocenyl benzhydrol [19] such as C, which can in turn derive from
piperonal and ferrocene. In particular, we reasoned that the benz-
hydrylation could be best achieved using conditions favoring a SN1
mechanism [20], analogously to the benzhydrylation of active
methlylenes pioneered by us some years ago [21]. Furthermore,
SN1-type nucleophilic substitutions on ferrocenyl derivatives are
known to take place via iron assistance with retention of configu-
ration [19aec]. As a consequence, control of the absolute configu-
ration of the stereogenic center at the benzylic position might be a
further bonus associated to this bioorganometallic approach.
However, initially we focused our efforts only on the synthesis of
racemic targets of type 2 lacking the lactone (D ring).
Benzhydrylic alcohol C was obtained via two alternative ap-
proaches from commercially available 6-bromopiperonal 3,
namely, either an oxidation/Friedel-Crafts acylation/reduction
sequence (Scheme 3, top) or a direct condensation with ferrocenyl
lithium (Scheme 3, down). The former synthesis started with a
Pinnick-type oxidation of aldehyde 3 to give the corresponding
carboxylic acid 3’ (85% y) by treatment with sodium chlorite in the
presence of phosphoric acid [22]. After standard formation the
corresponding acid chloride, Friedel-Crafts acylation with ferrocene
gave the diaryl ketone 3’’. Finally, LiAlH4 reduction gave alcohol C
(47% y). This sequence suffered from low yields, including genera-
tion of some debrominated alcohol C′ during the last reductive step
[23]. The second, more straightforward, approach gave alcohol C in
one step by reaction between ferrocenyl lithium [24], and aldehyde
3 (44% y). Although the latter approach is the one recommended,
the former route may be reconsidered for a future enantiopure
synthesis [25].
ER , show resistance to tamoxifen and a strong antiproliferative
a
effect with ferrocifens, which suggests that ferrocifen and tamox-
ifen here act through different ways. Further studies have shown
that the ferrocenyl moiety, by virtue of its reversible redox
behavior, induced oxidative stress in the cell, catalyzing production
of reactive oxygen species (ROS) [13]. Since that breakthrough,
other pharmaceuticals were modified in a similar manner, giving
rise to new bioactive organometallic compounds [14]. An example
of the above strategy is ferroquine, an innovative antimalarial drug,
currently at Phase II clinical trial at Sanofi-Aventis [15]. Due to their
peculiar properties, such as increased lipophilicity and bulkiness
with respect to the original drugs, these new conjugates allow
targeting of different sites in the biological medium. In line with the
above concept, we envisioned to prepare ferrocenyl podophyllo-
toxin analogs, either via hemisynthesis, by simply esterifying the
hydroxyl group at C-4 with the ferroceny moiety (1) (Fig. 2, left), or
by incorporating the organometallic sandwich in place of ring E in a
structure of type 2 (Fig. 2, right).
2. Results and discussion
Derivative 1 was straightforwardly obtained in 60% yield from
native podophyllotoxin by treatment with ferrocenoyl chloride
[16], Et3N, and catalytic amount of DMAP (Scheme 1).
The strategy to targets such as 2 is more complex and requires a
Substitution of alcohol C with b-dicarbonyl derivatives was then
tackled. The acid promoted alkylation of benzhydrols is known to
proceed via a SN1 mechanism [20], the corresponding carbenium
ion being highly stabilized by the two aromatic rings. Indeed, after a
brief experimentation, we found that reaction between ethyl ace-
toacetate and alcohol C in the presence of catalytic pTsOH (5 mol%)
in refluxing CH2Cl2 was the best choice, affording the expected
keto-ester 4 (75% y) (Scheme 4). Other combinations using malo-
nates instead of acetoacetates and Lewis acids (LA) or Brønsted
acids (HA) other than pTsOH gave either lower yields or no reaction
at all [26]. The subsequent allylation of 4 turned out to be trou-
blesome. Standard conditions of Pd-catalyzed conditions [allyl ac-
etate (2.5 equiv), Pd(OAc)2 (10 mol%), dppe (20 mol%), NaH (1.3
Fig. 2. Targeted ferrocenyl analogs of podophyllotoxin.
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Scheme 2. Retrosynthetic approach to the ferrocenyl analog of podophyllotoxin 2.
Scheme 3. Synthesis of o-bromo-sesamyl ferrocenyl alcohol C.
^
Scheme 4. Alkylation of benzydryl alcohol C and subsequent allylation of the resulting a-dicarbonyl derivative 4.
equiv)] gave back mainly unreacted starting material and only
to perform the alkylation from the “pre-allylated”
b-keto-ester 6
minor amounts of the desired adduct. A more classical allylation of
the sodium enolate of 4 with allyl iodide gave more promising re-
sults, which could be improved when working in the presence of
the 15-C-5 crown ether. In this case, the allylated product 5 could be
obtained in up to 50% yield, although the reaction was not easily
reproducible. The lack of reactivity of 4 may be due to steric hin-
drance of the ferrocenyl moiety.
[27]. Such a variant would render the synthesis more convergent
with respect to the previous plan, though requiring a challenging
benzhydrylation with formation of a quaternary-center. In the
event, use of the same acidic conditions as previously used to form
4, gave the targeted compound 5 in 35% yield, the main product
being the symmetric ether 7 (50% y) (Scheme 5, conditions a). This
result suggests that under these conditions, unionized benzhydrol
competes with the enol of 6 in the addition to the transient
In light of the difficulties to allylate intermediate 4, we decided
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M. Beauperin et al. / Journal of Organometallic Chemistry xxx (2017) 1e8
^
Scheme 5. Alkylation of benzhydryl alcohol C with the allylated a-dicarbonyl 6: three approaches compared.
carbenium ion. Although under HA or LA catalysis the symmetric
ether is in principle susceptible to give back the corresponding
carbenium ion [21,28], we were not able to exploit this prospective
equilibrium to obtain an alternative access to 5. C-C bond formation
via the Mitsunobu methodology is possible, provided that the pKa
of the C-pronucleophile is sufficiently low [29], and variants of the
original [DEAD/TPP] system have been developed [30] to this pur-
pose. For example, Tsunoda and co-workers [30a] used 1,1’-(azo-
dicarbonyl)dipiperidine (ADDP)/tributylphosphine system to
promote the reaction between diethyl malonate and benzylic
alcohol. Under these conditions, 5 was obtained in a 35% yield after
3 days at room temperature (Scheme 5, conditions b). Although this
result appeared promising, it still did not compare favorably with
the previous strategies. Finally, we found that conversion of C into
the corresponding chloride, followed by in situ treatment with the
sodium enolate of 6 gave the desired 5 in 65% yield (Scheme 5,
conditions c). Importantly, during chloride formation, HCl scav-
enging with 2,6-lutidine was necessary to inhibit formation of
dimer 7.
Intramolecular palladium-catalyzed Mizoroki-Heck cyclization
was next studied. The reaction proceeded satisfactorily under
classical conditions [17] [Pd(OAc)2 (10 mol%), dppe (20 mol%),
K2CO3 (2equiv), DMF, 130 ꢀC], providing the exocyclic alkene 8 in
84% yield (Scheme 6). The following planned retro-Claisen reaction
was achieved straightforwardly by treatment with EtONa in a
refluxing EtOH/THF, which gave the expected ester 9 in 95% yield
[31]. Conversion of the methylidene into the key g-oxo-ester A was
then easily accomplished in 60% overall yield via osmium-catalyzed
cis-dihydroxylation of 9 followed by NaIO4 cleavage [32]. The acid
form of the g-oxo-ester derivative A, lacking the ferrocenyl tail, has
already been identified as an advanced precursor to podophyllo-
toxin by Kende and coworkers [18], who were able to obtain pic-
ropodophyllone by treatment with formaldehyde and NaOH [33].
Unfortunately, all attempts to further functionalize intermediate A,
so as to add ring D, met with failure. Nevertheless, this study
enabled us to have in hand a novel molecule incorporating rings A,
B, and C of podophyllotoxin and carrying a ferrocenyl moiety in
place of ring E. Accordingly, A (R ¼ Et) was directly submitted to
NaBH4 reduction [34], and the resulting alcohol 2 (R ¼ Et) was sent
Scheme 6. Construction of ring C and subsequent conversion into the targeted analog.
for antiproliferative tests.
Three samples have been tested on the two breast cancer cell
lines: MCF-7 and MDA-MB-231. Podophyllotoxin was tested as a
reference, together with the O-ferrocenyl-podophyllotoxin (OFCP)
analog 1 and the alcohol 2 (R ¼ Et) (Table 1) [35].
Podophyllotoxin was found very active against both cancer cell
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Table 1
under nitrogen atmosphere. Thin layer chromatography was per-
formed on Merck 60 F254 silica gel and revealed with an ultra-
IC50 values of compounds on the hormone-dependent (MCF-7) and hormone-
independent (MDA-MB-231) breast cancer cell lines.
violet lamp (
l
¼ 254 nm) and a staining reagent (KMnO4, vanillin
Compound
MCF-7
(IC50
M)a
MDA-MB-231
or para-anisaldehyde). Merck Geduran SI 60 silica gel (40e63
mm)
m
(IC50 mM)a
was used for flash column chromatography. Solution NMR spectra
(1H and 13C) were recorded on a Bruker AVANCE 300, 400 or
600 MHZ spectrometer. 1H frequency of 300, 400 or 600 MHz,
respectively; 13C frequency of 75, 101 or 151 MHz. Chemical shifts
Podophyllotoxin
OFCP 1
“Alcohol 2 (R ¼ Et)”
0.01 0.00
0.93 0.07
39.75 2.00
0.01 0.00
0.43 0.03
27.6 2.40
a
Mean of two separate experiments.
(d) are given in ppm CDCl3 residual chloroform signal as reference.
IR spectra were recorded with a Tensor 27 (ATR diamond) Bruker
spectrometer. Only the most important bands were reported, in
wavenumbers ῡ (cmꢁ1). NMR and IR spectroscopy experiments
were performed at 300 K. HRMS spectra were recorded at the
lines (IC50 0.01
ferrocenyl moiety into the molecule, the cytotoxicity is reduced;
the IC50 values of OFCP 1 were 0.93 M for MCF-7 and 0.43 M for
mM) proving its high cytotoxicity. By incorporating a
m
m
ꢀ
Institut Parisien de Chimie Moleculaire (FR 2769) of UPMC (elec-
MDA-MB-231 which is in the average values generally found for
ferrocifens. These values are still satisfactory and may justify
further studies. The reduced cytotoxicity of 1 as compared to the
organic precursor is reminiscent to the result obtained with fer-
rocenyl modification of the extremely toxic illudin [36]. An
organometallic modification decreases its toxicity on fibroblasts
and increases its selectivity on cancer cells. Compound 1 could be
easier to use than podophyllotoxin. By contrast to 1, the alcohol 2
shows high IC50 proving that 2 is much less active than 1. It is
interesting to note that the organic moiety of 2 is different from
podophyllotoxin molecule.
trospray source). Cytotoxicity measurements on MCF-7 and MDA-
ꢁ
MB-231 breast cancer cells were performed ImaGIF Ciblotheque
Cellulaire (Institut de Chimie des Substances Naturelles).
Synthesis and analytical data of some intermediates (3′ and 300)
and by-products (C′ and 7) are described only in the SI.
4.1. O-Ferrocenylpodophyllotoxin 1
To a suspension of ferrocenylcarboxylic acid (60 mg, 0.26 mmol,
3 equiv) in 1 mL of dry CH2Cl2 was added at room temperature
oxalyl chloride (225 mL, 2.65 mmol, 27 equiv). After 30 min at room
In the multitargeting ferrocifen series the cytotoxicity is mainly
due so far to the redox primer {ferrocenyl-enedphenol} producing
ROS and able to delocalize the initial radical cation and generate
electrophilic quinone methides at the mitochondrial level [14a].
When the ferrocenyl phenol species are unconjugated the anti-
cancer effect decreases [37]. In the present case the organometallic
motifs are different from this arrangement but this type of oxida-
tive effect can be invoked to explain the results. The above redox
ferrocifen motif is not unique in order to modulate the anticancer
effects in a structure bearing a ferrocenyl group. Indeed, the recent
literature reports other primers related to our original concept,
producing similar effects in which the central electronic conduit in
adjacent position to a ferrocenyl species is a naphtyl group or an
ene- 2,5-piperazinedione unit [38]. Unveiling such an effect ex-
pands our original discovery and may be of interest for future de-
velopments of organometallic antitumor species.
temperature, the solution took a deep red color. The mixture was
concentrated in vaccuo to remove excess oxalyl chloride. Podo-
phyllotoxin (38 mg, 90
mmol, 1 equiv) was solubilizedequiv in
1.5 mL of dry CH2Cl2 and Et3N (15
mL, 0.11 mmol, 1.2 equiv) was
added. To this mixture was added at 0 ꢀC ferrocenoyl chloride in
2 mL of CH2Cl2. Then a few crystals of DMAP were added and the
mixture was stirred at 0 ꢀC for 30 min and at room temperature for
1 h. Reaction was quenched by addition of water, extracted with
CH2Cl2 (3ꢂ), washed with diluted HCl (~0.1 N), dried over MgSO4
and concentrated under vacuum. The crude product was purified
by preparative TLC on silica (AcOEt/Cyclohexane 2/3) to yield 35 mg
of the desired compound as an orange powder (60%). 1H NMR
(400 MHz, CDCl3):
d (ppm) 6.90 (s, 1H), 6.58 (s, 1H), 6.44 (s, 2H),
6.04e5.97 (m, 3H), 4.85 (dt, J ¼ 2.5, 1.3 Hz, 1H), 4.81 (dt, J ¼ 2.5,
1.3 Hz, 1H), 4.64 (d, J ¼ 4.3 Hz, 1H) 4.50e4.44 (m, 3H), 4.30 (m, 1H),
4.25 (s, 5H), 3.81 (s, 3H), 3.80 (s, 6H), 3.02e2.87 (m, 2H). 13C NMR
(101 MHz, CDCl3):
d (ppm) 173.8, 172.6, 152.8, 148.3, 147,8, 137.4,
3. Conclusion
135.1, 132.5, 129.0, 109.9, 108.4, 107.1, 101.8, 73.5, 72.1, 72.0, 71.8,
70.4, 70.3, 70.0, 61.0, 56.3, 45.8, 43.9, 39.1. IR (neat, cmꢁ1): 1780,
1711, 1485, 1240, 1128. Exact mass (C33H30FeO9): calculated
649.1132 (M þ Na)þ, measured 649.1121.
In this study we report the synthesis of two new podophyllo-
toxin analogs incorporating a ferrocenyl moiety and the pre-
liminary antiproliferative tests of these conjugates on two breast
cancer lines. While the former compound has been straightfor-
wardly obtained by esterification between podophyllotoxin and
ferrocenecarboxylic acid, the latter molecule, incorporating rings A,
B and C of podophyllotoxin and carrying the ferrocenyl appendage
in place of ring E of podophyllotoxin, required a 6-step synthesis
starting from 6-bromopiperonal and ferrocene. Key steps in the
synthesis were a challenging benzhydrylation generating a qua-
ternary center, and an intramolecular Mizoroki-Heck reaction,
which formed ring C of the target molecule. Such original struc-
tures have been discussed in terms of the importance of ferrocenyl
conjugated motifs to generate antiproliferative effects.
4.2. (6-Bromobenzo[1,3]dioxol-5-yl)(pherrocenyl)methanol C
4.2.1. First synthesis
To a suspension of LiAlH4 (138.2 mg, 3.64 mmol, 3 equiv) in 2 mL
THF at - 78 ꢀC was added dropwise a solution of 3’’ (505.3 mg,
1.23 mmol,1 equiv) in 3 mL THF. The mixture was stirred 45 min at -
78 ꢀC, quenched by a saturated aqueous solution of NH4Cl and
extracted with Et2O. The organic layer was washed with brine,
dried over MgSO4 and concentrated under vacuum. The crude
product was purified by flash chromatography on silica (AcOEt/
Cyclohexane 1:9) to yield 236.4 mg (47%) of C and 62 mg (10%) of C’.
4. Experimental section
4.2.2. Second synthesis
To a solution of ferrocene (1.86 g, 10 mmol, 1.2 equiv) in 10 mL of
a 1:1 mixture of THF and hexane, was added dropwise at 0 ꢀC a
solution of tBuLi (1.7 M in hexanes, 5.9 mL, 1.2 equiv). After
30 min at 0 ꢀC, the ice bath was removed and the mixture was
placed in an acetone/N2 liquid bath. Then, 6-bromopiperonal 3
Reactions were carried out under argon atmosphere. All re-
agents were used as obtained from commercial suppliers.
Dichloromethane and DMF were dried on a Braun purification
system MB SPS-800. THF was distilled over sodium/benzophenone
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6
(1.83 g, 8 mmol,1 equiv) in 20 mL of THF was added dropwise to the
dark red solution. After 1 h the reaction mixture was quenched by a
saturated aqueous solution of NH4Cl and extracted with Et2O. The
organic layer was washed with brine, dried over MgSO4 and
concentrated under vacuum. The crude product was purified by
flash chromatography on silica (AcOEt/Cyclohexane from 5/95 to
6.02e6.01 (m, 2H, diast. 2), 5.65e5.39 (m, 2H, diast.1 and 2), 5.37 (s,
1H, diast. 1), 5.35 (s, 1H, diast. 2), 4.97e4.86 (m, 4H, diast. 1 and 2),
4.39e3.83 (m, 12H, diast. 1 and 2), 3.94 (s, 5H, diast. 1), 3.92 (s, 5H,
diast. 2), 2.57e2.44 (m, 2H, diast. 1), 2.42e2.31 (m, 2H, diast. 2),
2.03 (s, 3H, diast. 1), 1.76 (s, 3H, diast. 2), 1.26 (t, J ¼ 7.2 Hz, 3H, diast.
1), 1.10 (t, J ¼ 7.2 Hz, 3H, diast. 2). 13C NMR (101 MHz, CDCl3, dia-
10/90) to yield 1.47 g (44%) of C. 1H NMR (400 MHz, CDCl3)
d
(ppm)
stereomeric mixture) d (ppm) 206.6 (diast. 1), 204.6 (diast. 2), 171.9
7.08 (s, 1H), 6.94 (s, 1H), 5.94 (d, J ¼ 1.4 Hz, 1H), 5.92 (d, J ¼ 1.4 Hz,
(diast. 1), 171.7 (diast. 2), 147.4, 147.3, 147.2, 147.1 (diast. 1 and 2),
133.8 (diast. 1), 133.1 (diast. 2), 132.8 (diast. 1), 132.2 (diast. 2), 118.8
(diast. 1), 118.0 (diast. 2), 117.5 (diast. 1 and 2), 112.8 (diast. 1 and 2),
110.1 (diast. 1), 101.0 (diast. 2), 102.1 (diast. 1), 102.0 (diast. 2), 88.1
(diast. 1), 87.9 (diast. 2), 71.4, 69.6, 69.0, 68.8, 68.4, 68.1, 67.7, 67.3
(diast. 1 and 2), 69.6 (diast. 1), 69.5 (diast. 2), 69.0 (diast. 1), 68.8
(diast. 2), 61.4 (diast. 1), 61.3 (diast. 2), 47.9 (diast. 1), 47.2 (diast. 2),
39.5 (diast. 1), 39.3 (diast. 2), 31.7 (diast. 1), 30.3 (diast. 2), 14.2
(diast. 1), 13.8 (diast. 2). IR (neat, cmꢁ1): 3079, 1730, 1700, 1638,
1503, 1478. Exact mass (C27H27BrFeO5): calculated 589.0285
(M þ Na)þ, measured 589.0301.
1H), 5.76 (d, J ¼ 3.0 Hz, 1H), 4.38e4.15 (m, 4H), 4.26 (s, 5H), 2.65 (d,
J ¼ 3.1 Hz,1H). 13C NMR (101 MHz, CDCl3)
d (ppm) 147.8,147.7, 136.1,
112.8, 112.5, 107.8, 101.8, 93.9, 70.5, 68,7, 68.4, 68.0, 67.7, 65.9. IR
(neat, cmꢁ1): 3559, 2914, 1498, 1470. Exact mass (C18H15O3FeBr):
calculated 436.94462 (M þ Na)þ, measured 436.94438.
4.3. Ethyl 2-((6-bromobenzo[1,3]dioxol-5-yl)(pherrocenyl)methyl)-
3-oxobutanoate 4
To a solution of C (1.3 g, 3 mmol, 1 equiv) in 4 mL of CH2Cl2 were
added ethyl acetoacetate (0.38 mL, 3 mmol, 1 equiv) and TsOH
(26 mg, 0.15 mmol, 5 mol%). The mixture was stirred at reflux
during 1 h until completion monitored by TLC, quenched by a
saturated aqueous solution of NaHCO3 and extracted with CH2Cl2.
The organic layer was washed with brine, dried over MgSO4 and
concentrated under vacuum. The crude product was purified by
flash chromatography on silica (AcOEt/Cyclohexane 2:8) to yield
934 mg (75%) of 4 as a 50/50 diastereomeric mixture. 1H RMN
4.5. Ethyl 6-acetyl-8-methylene-5-pherrocenyl-5,6,7,8-
tetrahydronaphtho[2,3-d][1,3]dioxole-6-carboxylate 8
To a solution of Pd(OAc)2 (28.0 mg, 0.12 mmol, 10 mol-%), dppe
(100.3 mg, 0.25 mmol, 20 mol-%) and K2CO3 (345.3 mg, 0.24 mmol,
2 equiv) in 2.3 mL of DMF was added 3 (706.2 mg, 1.25 mmol, 1
equiv) in 16.3 mL of DMF and the mixture was heated at 130 ꢀC for
18 h. The reaction was quenched by a saturated aqueous solution of
NH4Cl and extracted with Et2O. The organic layer was washed
intensively with diluted HCl (0.1 N), then with brine, dried over
MgSO4 and concentrated under vacuum. The crude product was
purified by flash chromatography on silica (AcOEt/Cyclohexane 15/
85) to yield 508.7 mg (84%) of 8 as a 60/40 diastereomeric mixture.
(300 MHz, CDCl3, diastereomeric mixture) d (ppm) 7.09 (s,1H, diast.
1), 7.08 (s,1H, diast. 2), 6.86 (s,1H, diast.1), 6.79 (s,1H, diast. 2), 6.01
(d, J ¼ 1.4 Hz, 2H, diast.1), 5.99 (d, J ¼ 1.3 Hz, 2H, diast. 2), 4.98e4.94
(m, 2H, diast. 1 and 2), 4.11e3.92 (m, 24H, diast.1 and 2), 2.08 (s, 6H,
diast. 1 and 2), 1.16 (t, J ¼ 7.2 Hz, 3H, diast. 1), 1.03 (t, J ¼ 7.3 Hz, 3H,
diast. 2). 13C NMR (101 MHz, CDCl3, diastereomeric mixture)
d
(ppm) 201.2 (diast. 1), 201.1 (diast. 2), 167.8 (diast. 1), 166.7 (diast.
1H NMR (300 MHz, CDCl3, diastereomeric mixture)
d (ppm) 7.11 (s,
2), 147.5 (diast. 1), 147.2 (diast. 2 et diast. 1), 146.9 (diast. 2), 134.7
(diast. 2), 133.9 (diast. 1), 115.8 (diast. 2), 115.4 (diast. 1), 112.7 (diast.
1), 112.6 (diast. 2), 108.3 (diast. 1), 108.1 (diast. 2), 101.9 (diast. 1),
101.8 (diast. 2), 89.6 (diast. 1), 89.5 (diast. 2), 69.9, 69.4, 68.8, 68.2,
68.1, 67.5, 66.9, 66.7 (diast. 1 et diast. 2), 65.6 (diast. 1), 65.3 (diast.
2), 61.5 (diast. 2), 61.3 (diast. 1), 43.1 (diast. 1), 42.8 (diast. 2), 30.9
(diast. 1), 28.1 (diast. 2), 14.0 (diast. 1), 13.8 (diast. 2). IR (neat,
cmꢁ1): 2901, 2981, 1731, 1503, 1477, 1221, 1153, 1035. Exact mass
(C24H23BrFeO5Na): calculated 548.9972 (M þ Na)þ, 548.9967
measured.
1H, minor diast.), 7.08 (s, 1H, major diast.), 7.03 (s, 1H, major diast.),
7.01 (s, 1H, minor diast.), 6.00 (t, J ¼ 1.2 Hz, 2H, major and minor
diast.), 5.96 (t, J ¼ 1.2 Hz, 2H, major and minor diast.), 5.45 (s, 2H,
major and minor diast.), 4.66e4.64 (m, 1H, minor diast.), 4.64e4.61
(m, 1H, major diast.), 4.27e3.93 (m, 12H, major and minor diast.),
4.10 (s, 5H, major diast.), 4.08 (s, 5H, minor diast.), 3.46e3.43 (m,
1H, minor diast.), 3.42e3.40 (m,1H, major diast.), 3.06e3.01 (m, 1H,
minor diast.), 3.00e2.95 (m, 1H, major diast.), 2.89e2.87 (m, 1H,
major diast.), 2.83e2.81 (m, 1H, minor diast.), 2.15 (s, 3H, minor
diast.), 2.10 (s, 3H, major diast.), 1.27 (t, J ¼ 7.1 Hz, 6H, major diast.),
1.04 (t, J ¼ 7.1 Hz, 6H, minor diast.). 13C NMR (75 MHz, CDCl3, dia-
4.4. Ethyl 2-acetyl-2-((6-bromobenzo[1,3]dioxol-5-yl)(pherrocenyl)
methyl)pent-4-enoate 5
stereomeric mixture) d (ppm) 204.7 (minor diast.), 202.9 (major
diast.), 170.0 (minor diast.), 169.8 (major diast.), 147.6, 147.5, 147.3,
147.2 (major and minor diast.), 138.8 (minor diast.), 138.5 (major
diast.), 132.1 (minor diast.), 131.6 (major diast.), 127.5 (major diast.),
127.4 (minor diast.) 110.5 (major diast.), 110.4 (minor diast.), 109.4
(major diast.), 109.2 (minor diast.), 103.4 (major diast.), 103.3 (mi-
nor diast.), 101.3 (major diast.), 101.2 (minor diast.), 90.2, 89.3, 69.4,
69.3, 69.0, 67.7, 67.0 (major and minor diast.), 66.3 (major diast.),
65.6 (minor diast.), 61.7 (major diast.), 61.6 (minor diast.), 45.6
(minor diast.), 45.1 (major diast.), 32.0 (minor diast.), 31.7 (major
diast.), 26.3 (minor diast.), 26.2 (major diast.), 14.1 (major diast.),
13.9 (minor diast.). IR (neat, cmꢁ1): 3087, 1737, 1713, 1503, 1480.
Exact mass (C27H26FeO5): calculated 509.1022 (M þ Na)þ, measured
509.1018.
4.4.1. Starting from the alcohol C, third essay (via chloride
intermediate)
To a solution of C (100 mg, 0.24 mmol, 1 equiv) in 1 mL of THF,
was added 2,6-lutidine (42
dropwise addition of oxalyl chloride (25
m
L, 0.36 mmol, 1.5 equiv.) followed by a
L, 0.29 mmol, 1.2 equiv).
m
The mixture was stirred at room temperature during 90 min.
Separately, ethyl 2-acetylpent-4-enoate (80 mg, 0.5 mmol, 2 equiv)
was added on a suspension of sodium hydride (23 mg, 0.57 mmol,
2.4 equiv) in 1 mL of THF. This solution was cannulated on the
solution of C. After overnight at room temperature, the reaction was
quenched by a saturated aqueous solution of NH4Cl and extracted
with Et2O. The organic layer was washed with a solution of HCl
0.1 N, then with brine, dried over MgSO4 and concentrated under
vacuum. The crude product was purified by flash chromatography
on silica (CH2Cl2/Cyclohexane 1:1) to yield 90 mg (65%) of 5 as a 50/
50 diastereomeric mixture. 1H RMN (400 MHz, CDCl3, diastereo-
4.6. Ethyl 8-methylene-5-pherrocenyl-5,6,7,8-tetrahydronaphtho
[2,3-d][1,3]dioxole-6-carboxylate 9
To a solution of sodium ethylate formed by reacting Na (30 mg,
1.3 mmol, 1.5 equiv) in 5 mL of absolute EtOH was added 8 (430 mg,
0.885 mmol, 1 equiv) in 5 mL THF. The mixture was brought to
meric mixture) d (ppm) 7.13 (s, 1H, diast. 1), 7.11 (s, 1H, diast. 2), 7.06
(s, 1H, diast. 1), 6.85 (s, 1H, diast. 2), 6.05e6.04 (m, 2H, diast. 1),
ꢀ
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M. Beauperin et al. / Journal of Organometallic Chemistry xxx (2017) 1e8
7
reflux for 3 h, then the reaction was quenched by addition of HCl
0.2 N and extracted with Et2O. The organic layer was washed with
brine, dried over MgSO4 and concentrated under vacuum. The
crude product was purified by flash chromatography on silica
(AcOEt/Cyclohexane 5/95e> 10/90) to yield 370 mg (95%) of ester 9
as a 65/35 diastereomeric mixture. 1H NMR (400 MHz, CDCl3, dia-
(major diast.), 102.1 (minor diast.), 101.9 (major diast.), 91.6 (major
diast.), 88.0 (minor diast.), 69.1, 69.0, 68.88, 68.6, 68.5, 67.7, 67.4,
67.3, 67.2, 66.6 (major and minor diast.), 61.2 (major diast.), 61.1
(minor diast.), 48.1 (major diast.), 46.1 (minor diast.), 42.1 (minor
diast.), 42.0 (major diast.), 35.4 (minor diast.), 35.2 (major diast.),
14.4 (minor diast.), 14.2 (major diast.). IR (neat, cmꢁ1): 1725, 1671,
1478, 1256. Exact mass (C24H22FeO5): calculated 469.0709
(M þ Na)þ, measured 469.0704.
stereomeric mixture)
d (ppm) 7.17 (s, 1H, minor diast.), 7.08 (s, 1H,
major diast.), 6.93 (s, 1H, minor diast.), 6.92 (s, 1H, major diast.),
6.01 (d, J ¼ 1.1 Hz, 1H, minor diast.), 6.00e5.98 (m, 1H, minor diast.),
5.96 (d, J ¼ 1.2 Hz, 1H, major diast.), 5.94 (d, J ¼ 1.1 Hz, 1H, major
diast.), 5.44e5.42 (m, 1H, minor diast.), 5.40e5.33 (m, 1H, major
diast.), 4.91e4.89 (m, 1H, minor diast.), 4.89e4.85 (m, 1H, major
diast.), 4.36e4.32 (m, 1H, major diast.), 4.30e4.29 (m, 1H, minor
diast.), 4.23e3.99 (m, 10H, major and minor diast.), 4.17 (s, 5H,
major diast.), 4.12 (s, 5H, minor diast.), 3.67e3.64 (m, 1H, major
diast.), 3.47e3.45 (m, 1H, minor diast.), 3.03e2.85 (m, 2H, major
and minor diast.), 2.81e2.52 (m, 4H, major and minor diast.),1.31 (t,
4.8. Ethyl 8-hydroxy-5-pherrocenyl-5,6,7,8-tetrahydronaphtho
[2,3-d][1,3]dioxole-6-carboxylate 2(R ¼ Et)
g-Oxo-ester A (80 mg, 0.18 mmol,1 equiv) was dissolved in EtOH
(5 mL) and THF (2 mL). The solution is canulated over NaBH4
(14 mg, 0.57 mmol, 3 equiv) in 2 mL EtOH. The mixture was stirred
at room temperature. The reaction progressed slowly. After 15 h
(overnight) starting material has disappeared but ester was
partially reducted. The reaction mixture was then purified by pre-
parative TLC (AcOEt/cyclohexane 2:3) to yield 20 mg (25%) of
alcohol 2 (R ¼ Et) as two isolated diastereoisomers (75/25). Second
product is the diol in mixture with degradation. 1H NMR (400 MHz,
J ¼ 7.1 Hz, 3H, minor diast.), 1.16 (t, J ¼ 7.1 Hz, 3H, major diast.). 13
C
NMR (101 MHz, CDCl3, diastereomeric mixture)
d (ppm) 173.9
(major diast.), 173.3 (minor diast.), 147.4, 147.2, 147.1, 146.9 (major
and minor diast.), 140.6 (minor diast.), 139.6 (major diast.), 133.2
(minor diast.), 131.2 (major diast.), 128.4 (minor diast.), 128.1 (major
diast.), 109.8 (major and minor diast.), 108.4 (major and minor
diast.), 103.9 (major and minor diast.), 101.2 (minor diast.), 101.1
(major diast.), 93.8, 89.7, 69.6, 69.3, 69.0, 68.8, 68.0, 67.9, 67.2, 66.9,
66.8, 66.3 (major and minor diast.), 60.7 (major diast.), 60.6 (minor
diast.), 47.2 (major diast., 45.7 (minor diast.), 42.9) (minor diast.,
41.2 (major diast.), 30.2 (major diast.), 28.4 (minor diast.), 14.4
(minor diast.), 14.3 (major diast.). IR (neat, cmꢁ1): 3085, 1729, 1503,
1480. Exact mass (C25H24FeO4): calculated 467.0916 (M þ Na)þ,
measured 467.0931.
CDCl3, major diast.):
d (ppm) 7.04 (s, 1H), 6.98 (s, 1H), 6.00 (d,
J ¼ 1.3 Hz, 1H), 5.97 (d, J ¼ 1.3 Hz, 1H), 4.74e4.64 (m, 1H), 4.25 (d,
J ¼ 3.8 Hz, 1H), 4.18e4.10 (m, 8H), 4.05e4.02 (m, 1H), 4.01e3.99 (m,
1H), 3.45e3.43 (m, 1H), 2.91 (ddd, J ¼ 12.5, 4.0, 2.6 Hz, 1H),
2.33e2.22 (m, 1H), 1.84 (d, J ¼ 7.9 Hz, 1H), 1.73 (ddd, J ¼ 13.4, 12.5
9.4 Hz, 1H 1.29 (t, J ¼ 8.2 Hz, 3H). 13C NMR (101 MHz, CDCl3, major
diast.): d (ppm) 173.3, 147.1, 146.7, 132.5, 131.4, 101.2, 91.1, 70.3, 69.1,
69.0, 68.1, 67.2, 66.7, 60.8, 45.4, 41.7, 30.2, 14.3. 1H NMR (400 MHz,
CDCl3, minor diast.): (ppm) 6.96 (s, 1H), 6.88 (s, 1H), 5.93 (d, 1H,
d
J ¼ 2.0 Hz), 4.79e4.70 (m,1H), 4.27 (d,1H, J ¼ 4.0 Hz), 4.23e4.06 (m,
10H), 3.81 (s, 1H), 3.49 (s, 1H), 3.18e3.11 (m, 1H), 2.30e2.21 (m, 1H),
1.94 (dd, J ¼ 8.2, 4.5 Hz, 1H), 1.62e1.50 (m, 1H), 1.25 (t, J ¼ 7.1 Hz,
4.7. Ethyl 8-oxo-5-pherrocenyl-5,6,7,8-tetrahydronaphtho[2,3-d]
[1,3]dioxole-6-carboxylate A
3H). 13C NMR (101 MHz, CDCl3, minor diast.):
d (ppm) 174.6, 147.2,
146.7, 131.4, 131.1, 109.7, 107.7, 101.1, 69.5, 69.2, 68.2, 67.2, 67.1, 66.4,
61.0, 51.0, 46.0, 39.6, 32.2, 14.4. IR (neat, cmꢁ1): 3519, 1716, 1480,
1226. Exact mass (C24H24FeO5): calculated 448.0968 (M þ Na)þ,
measured 448.0979.
To a solution of ester 9 (550 mg, 1.24 mmol, 1 equiv) in a 9:1
mixture of THF/H2O (30 mL) was added N-methylmorpholine oxide
monohydrate (370 mg, 2.74, 2.2 equiv) and OsCl3 (40 mg,
0.12 mmol,10 mol-%). The mixture was stirred at room temperature
for 20 h, quenched with a 50% aqueous solution of NaHSO3, and
extracted with AcOEt. The organic phase was washed with brine,
dried over MgSO4 and concentrated under vacuum. The crude
product was solubilised in 30 mL of a 2:1 mixture of acetone and
water and NaIO4 (630 mg, 2.95 mmol, 2.4 equiv) was added. After
3 h at room temperature, the reaction mixture was quenched with a
saturated aqueous solution of Na2S2O3, and extracted with Et2O.
The organic phase was washed with brine, dried over MgSO4 and
concentrated under vacuum. The crude product was purified by
flash chromatography on silica (AcOEt/Cyclohexane 5/95) to yield
330 mg (60%) of A as a 65/35 diastereomeric mixture. 1H NMR
4.9. Cell culture and cell proliferation assay
The breast adenocarcinoma cell lines MDA-MB-231 and MCF-7
were obtained respectively from ATCC and Dr Matthias Kassack
(Bonn, Germany). Cells were grown in RPMI medium supple-
mented with 10% fetal calf serum, in the presence of penicilline,
streptomycine and fungizone in 75 cm2 flask under 5% CO2. Cells
were plated in 96-well tissue culture plates in 200
treated 24 h later with 2 l stock solution of compounds dissolved
in DMSO using Biomek 3000 (Beckman-Coulter). Controls
ml medium and
m
a
received the same volume of DMSO (1% final volume). After 72 h
exposure, MTS reagent (Promega) was added and incubated for 3 h
at 37 ꢀC: the absorbance was monitored at 490 nm and results
expressed as the inhibition of cell proliferation calculated as the
ratio [(1-(OD490 treated/OD490 control)) ꢂ 100] in triplicate ex-
periments. For IC50 determination [50% inhibition of cell prolifer-
ation], cells were incubated for 72 h following the same protocol
(300 MHz, CDCl3, diastereomeric mixture)
d 7.49 (s, 1H, minor
diast.), 7.47 (s,1H, major diast.), 7.04 (s,1H, minor diast.), 6.95 (s,1H,
major diast.), 6.10 (d, J ¼ 1.2 Hz, 1H, minor diast.), 6.08e6.07 (m, 2H,
major and minor diast.), 6.04 (d, J ¼ 1.3 Hz, 1H, major diast.),
4.50e4.47 (m, 2H, major and minor diast.), 4.28e4.00 (m, 21H,
major and minor diast.), 3.47e3.43 (m, 1H, major diast.), 3.34e3.26
(m, 1H, minor diast.), 3.14 (dt, J ¼ 5.1, 2.5 Hz, 1H, major diast.),
2.84e2.80 (m, 1H, minor diast.), 2.76e2.75 (m, 1H, major diast.),
2.64e2.43 (m, 2H, major and minor diast.), 1.29 (t, J ¼ 7.2 Hz, 3H,
minor diast.) 1.11 (t, J ¼ 7.1 Hz, 3H, major diast.). 13C NMR (101 MHz,
with compound concentrations ranged 5 nM to 100
duplicate experiments.
mM in separate
Acknowledgements
CDCl3, diastereomeric mixture)
d (ppm) 195.5 (minor diast.), 194.0
(major diast.), 172.8 (major diast.), 171.9 (minor diast.), 152.2 (major
and minor diast.), 147.8 (major and minor diast.), 141.5 (minor
diast.), 139.2 (major diast.), 127.6 (minor diast.), 127.3 (major diast.),
109.3 (major diast.), 109.2 (minor diast.), 106.5 (minor diast.), 106.4
We thank Yasmine Reviriot for her contribution in preliminary
experiments and Omar Khaled for HRMS analyses. CNRS, UPMC,
and LabEx MiChem part of French state funds managed by the ANR
within the Investissements d'Avenir programme under reference
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j.jorganchem.2017.02.005

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M. Beauperin et al. / Journal of Organometallic Chemistry xxx (2017) 1e8
8
S. Ladeira, E. Benoist, Appl. Organometal. Chem. 25 (2011) 680.
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ANR-11-IDEX-0004-02 for financial support. Support through
CMST COST Action, CM1205 (CARISMA) is also gratefully
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respect to C-4.
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Please cite this article in press as: M. Beauperin, et al., Journal of Organometallic Chemistry (2017), http://dx.doi.org/10.1016/
j.jorganchem.2017.02.005