Enantioselective Synthesis of Planar Chiral Ferrocifens that Show Chiral Discrimination in Antiproliferative Activity on Breast Cancer Cells

Article abstract of DOI:10.1002/cbic.202000311

The design and first enantioselective synthesis of a series of chiral ferrocifens and ferrociphenols was realised by enantioselective palladium-catalysed intramolecular direct C?H bond activation followed by McMurry coupling. Biological evaluation revealed moderate anticancer activities on breast cancer cells and evidence of chiral discrimination between enantiomers. Treatment of the novel ferrocifens with Ag₂O revealed that these systems are unable to form a neutral quinone methide, yet still demonstrate marked antiproliferative properties against both the hormone-dependent MCF-7 and hormone-independent MDA-MB-231 cell lines. This bioactivity arises from two mechanisms: Fenton-type chemistry and the anti-estrogenic activity associated with the tamoxifen-like structure.

Full text of DOI:10.1002/cbic.202000311

Combining Chemistry and Biology
Accepted Article
Title: Enantioselective Synthesis of Planar Chiral Ferrocifens that Show
Chiral Discrimination in Antiproliferative Activity on Breast Cancer
Cells
Authors: Laura Cunningham, Yong Wang, Chris Nottingham, Jammah
Pagsulingan, Gérard Jaouen, Michael McGlinchey, and
Patrick Jerome Guiry
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To be cited as: ChemBioChem 10.1002/cbic.202000311
Link to VoR: https://doi.org/10.1002/cbic.202000311
01/2020

10.1002/cbic.202000311
ChemBioChem
FULL PAPER
Enantioselective Synthesis of Planar Chiral Ferrocifens that Show
Chiral Discrimination in Antiproliferative Activity on Breast
Cancer Cells
Laura Cunningham,[a,b] Yong Wang,[c,d] Chris Nottingham,[a] Jammah Pagsulingan,[a] Gérard Jaouen,[c,d]
Michael J. McGlinchey,[a] Patrick J. Guiry*[a,b]
[a] Centre for Synthesis and Chemical Biology, School of Chemistry
University College Dublin, Belfield Dublin 4, Ireland
Email: p.guiry@ucd.ie, http://www.guiryresearchgroup.com
[b] Synthesis and Solid-State Pharmaceutical Centre (SSPC), School of Chemistry,
University College Dublin, Belfield, Dublin 4, Ireland
[c] PSL, Chimie ParisTech, 11 rue Pierre et Marie Curie, F-75005 Paris, France
[d] Sorbonne Université, UPMC Univ Paris 6, UMR 8232 CNRS, IPCM Place Jussieu, F-75005 Paris, France
In the realm of bioorganometallic chemistry,[3-8] the ferrocifen
Abstract: The design and first enantioselective synthesis of a series
system continues to attract significant attention.[9-16] These
of chiral ferrocifens and ferrociphenols was realised via
molecules possess a ferrocenyl-ene-p-phenol motif,[17,18] and a
enantioselective palladium-catalysed intramolecular direct C-H bond
basic dimethylaminoalkoxy chain, as in 3. They are readily
activation followed by McMurry coupling. Biological evaluation
prepared by McMurry coupling of a ferrocenyl ketone and an
revealed moderate anticancer activities on breast cancer cells and
appropriate benzophenone, typically in low to moderate yield (10-
evidence of chiral discrimination between enantiomers. Treatment of
53%) followed by incorporation of the basic chain (Scheme
these novel ferrocifens with Ag2O revealed that these systems are
1).[19,20] Subsequently, it was found that in many cases the
unable to form a neutral quinone methide, yet still demonstrate
precursor ferrociphenols, 2, which lack the basic side chain, also
marked antiproliferative properties versus both the hormone-
exhibit marked antiproliferative properties.[21]
dependent MCF-7 and hormone-independent MDA-MB-231 cell lines.
This bioactivity arises from two mechanisms: Fenton-type chemistry
and the anti-estrogenic activity associated with the tamoxifen-like
structure.
Introduction
Despite its world-wide status as the most widely prescribed
medication to combat breast cancer, tamoxifen 1a (Figure 1) is
only efficacious against hormone-dependent cancer cell lines that
over-express estrogen receptors (ER+), which make up 70% of
all breast cancers.[1] The remaining 30%, however, are
impervious to treatment with selective estrogen receptor
modulators (SERMs) such as tamoxifen and often require the use
of harsh non-targeted therapies. Ferrociphenols, 2, and
ferrocifens, 3, (Figure 1), are ferrocene-containing analogues of
tamoxifen which have been extensively investigated in the last 25
years due to their dramatic antiproliferative activity not only
against ER+ cell lines, but also hormone-independent (ER-)
Scheme 1. Preparation of ferrociphenols, 2, and ferrocifens, 3.
cancers.[2]
Ferrociphenols operate not only as the result of reversible redox
of the ferrocenyl moiety (Fe2+ ↔ Fe3+) which leads to the
generation of reactive oxygen species (ROS), in particular
hydroxyl radicals, but also by the formation of quinone methides
(QMs) as primary metabolites.[2,22-24] These QMs are highly
electrophilic and react with overexpressed nucleophilic peptides
or proteins in the cell, such as those bearing thiols or selenols
Figure 1. Structures of tamoxifen, 1a, hydroxytamoxifen (OH-Tam) 1b,
(Scheme 2), and can lead to cell death by interference with
oxidative stress or inactivation of enzymes.[25] Treatment of
ferrociphenols, 2, and ferrocifens, (Fc-Tam and Fc-OH-Tam) 3.
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ferrociphenols or ferrocifens, either chemically with Ag2O, or
enzymatically by incubation with horseradish peroxidase (HRP)
or rat liver microsomes and NADPH, provides a convenient
laboratory route to the corresponding QMs.[22-24]
positioned on the α- or ß-face of the steroid, could be separated
and unambiguously distinguished by NMR spectroscopy (Figure
3).[33] Subsequently, it was shown that the relative binding affinity
(RBA) values of these α- and ß-isomers for the estradiol receptor
site were strikingly different (28% v. 2%, respectively), and
provided the first example of such facial discrimination.[3]
Figure 3. Planar chiral estradiol analogues which demonstrate facial
Scheme 2. Reaction of a ferrocenyl quinone methide with a thiol (e.g.
discrimination of the estradiol receptor.
glutathione) or a selenol (e.g. thioredoxin reductase).
Continuing in the steroid field, the diastereomers of
o-formylcyclopentadienyl metal complexes of 17α-ethynyl-
estradiol, (Rp)-9 and (Sp)-9, (Figure 4) were prepared in pure form
and their bioactivity evaluated. In the ferrocenyl and manganese
complexes, the affinity of the Rp-diastereomers for the estradiol α
receptor is almost twice that of their Sp-counterparts, clearly
exhibiting receptor discrimination between organometallic
systems possessing planar chirality. However, these complexes
show a proliferative effect on MCF-7 breast cancer cells,
indicating estrogenic behaviour.[34]
A wide range of ferrocifens and ferrociphenols (> 300) has been
prepared and their bioactivity evaluated. In the early phase of
these studies, the molecules all possessed an ethyl substituent,
as in hydroxytamoxifen – the current first line adjuvant therapy for
hormone-dependent breast cancers – on which they were
originally modelled.[1] Subsequent work revealed that
incorporation of hydroxyalkyl[22-24] (or, even better, imidoalkyl[26,27]
)
substituents dramatically lowered IC50 values into the low
nanomolar range, and also greatly extended their spectrum of
activity to include lung, prostate, renal, colon, ovarian and CNS
tumours, as well as leukemia and melanomas.[24] However, in all
cases, except for those in which the ferrocenyl moiety possessed
[28]
a polymethylene chain, as in 5,
and also the ansa systems,
6,[29-32] the ferrocenyl unit remained constant. We here report the
first such molecules in which the ferrocene moiety is now derived
from ferroceno[2,3]indene, as in 7. The novelty here is that the
precursor ketone can be conveniently prepared in either
enantiomerically pure form prior to its use in the McMurry coupling
procedure. Hence, a number of optically active ferrocifens and
ferrociphenols have been synthesised for the first time and their
bioactivity evaluated.
Figure 4. Planar chiral ferrocenyl estradiol derivative diastereomers which
demonstrate distinct RBA for the ER.
In the area of currently prescribed metallodrugs, the enantiomers
of ferroquine, the organometallic antimalaria drug derived by
incorporation of a ferrocenyl unit into the chloroquine structure,
have been independently tested to probe whether planar chirality
has a beneficial effect. However, their bioactivity did not differ
substantially, indeed the racemic version now widely used
clinically is more effective.[35] Finally, we note that the ferrocenyl-
containing platensimycin derivatives were each synthesised in
enantiomerically pure form and tested against a range of
methicilline- or vancomycin- resistant bacterial strains;
unfortunately, they showed no bioactivity up to 200 μg/mL[36]
With these results in mind, it seemed highly likely that each
enantiomeric pair of planar chiral ferrocifens will effect different
IC50 values, given that the two cases described above in which the
sense of planar chirality influences relative binding affinities were
those involving the estradiol scaffold. To this end, we sought to
prepare a series of ferrocifen analogues in which the planar
chirality is controlled to afford enantiomeric pairs of ferrocifens
Figure 2. Ferrociphenols and ferrocifens in which the ferrocenyl moiety has
been modified, including one target enantiopure chiral ferrocifen, 7, (only one
enantiomeric series shown).
We note several earlier studies in which the influence of planar
chirality on bioactivity was investigated. In 1985, it was reported
that the diastereomers of 8, whereby the Cr(CO)3 moiety was
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10.1002/cbic.202000311
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and ferrociphenols and compare their biological effect on
hormone-dependent and -independent breast cancer cell lines.
With both R- and S-forms of the required ferrocenyl ketone in
hand, we next prepared the necessary benzophenone coupling
partners for the McMurry coupling. Unlike most previous reports
of the synthesis of ferrocenyl-polyphenols by this method,[2,28,29] in
our hands unprotected phenolic groups were found to hinder the
reaction. Indeed, up to 11 different products, most of them
unwanted, can be generated from the McMurry coupling of two
unique ketones; moreover, the desired ferrociphenol-type
compounds were not isolable. However, TBS protection of the
hydroxy groups not only significantly increased the yields of the
McMurry hetero-coupling products from trace amounts to up to
41%, but also enabled purification of the target molecules
(Scheme 4).
Results and Discussion
Synthetic aspects
Chiral ferrocifens of this novel type were prepared via McMurry
coupling of the corresponding benzophenone and enantiopure
planar chiral ferrocenyl ketone. The design of these novel
analogues is based on the previous bioactivity profiles of related
compounds 5 and 6 (Figure 2). While acyclic ferrocifens of the
type 3 exhibit considerable efficacy against cancers for which
tamoxifen proved ineffective, ansa-ferrocifens 6 demonstrate up
to seven-fold reductions in IC50 values versus their acyclic
analogues.[29] Shortly after this observation, other ferrocifens,
such as 5, derived from ferrocene fused to monocyclic ketones
were also studied; such molecules are planar chiral.[28] However,
they were prepared only in a racemic fashion, whereas it is, of
course, of particular interest to be able to prepare and test
separately each enantiomer of a novel biologically active
compound. Chiral ferrocifens of type 7 were selected as ideal
targets since methodology to access the related ferrocenyl ketone
enantioselectively has previously been employed in our
laboratory,[37] based on methodology developed by Gu and
You,[38,39] thus enabling an efficient route to the first reported
enantiopure chiral ferrocifens.
R2
1. Zn dust (10 eq)
O
TiCl4 (5 eq)
Pyridine (2.6 eq)
O
+
Fe
Fe
R1
R2
2. TBAF
R1
(R)-11
(R)-7
7-41%
R1 = H, OTBS
R2 = OTBS, O(CH2)2NMe2
R1 = H, OH
R2 = OH, O(CH2)2NMe2
Scheme 4. Route from enantiopure ketone 11 to ferrocifen 7. In this case, only
the synthesis of the (R)-enantiomer is depicted.
In an attempt at rational design of our initial library of enantiopure
ferrociphenols and ferrocifens, we selected a number of target
molecules, shown in Figure 5, based on key functionalities
identified as being significant in previous research.[2,40] Ferrocifen
7a was chosen because the dimethylaminoethoxy group has
previously been shown to confer a greater ER binding affinity on
ferrocifen derivatives compared to those lacking it.[41] Both
enantiomers of 7a were prepared to determine whether one
elicited a greater response. The 4'-hydroxyferrocifen derivative,
7b, was also selected, since the phenol precursors to QMs exhibit
superior anti-estrogenic activity to that of the non-hydroxylated
parent compounds.[6,9,10] The monophenol 7c, was chosen to
afford insight into the significance of removing the
dimethylaminoethoxy basic chain. The bisphenol 7d was targeted
as it exists solely as enantiomers, in contrast to 7a-7c which exist
as E/Z-mixtures.
Despite the target compounds appearing to be formed in modest
to low yields, it is noteworthy that as a result of the large number
of by-products from the McMurry coupling, and the resulting
inherently challenging purification process, the yields reported
here are similar to those reported for other analogues prepared in
this fashion. Indeed, the typical yields of such reactions are below
30%.[28,29]
Cs2CO3 (2 eq.)
Cs2CO3 (2 eq.)
Pd(OAc)2 (2 mol %)
(R)-BINAP (4 mol %)
Pivalic Acid (30 %)
Pd(OAc)2 (2 mol %)
(S)-BINAP (4 mol %)
Pivalic Acid (30 %)
I
O
O
O
Fe
Fe
Fe
Toluene, 100 oC, 16 h
Toluene, 100 oC, 16 h
(S)-11
10
(R)-11
99% yield
99% ee
99% yield
99% ee
Scheme 3. Enantioselective syntheses of (S)-11 and (R)-11.
The aryl halide substrate 10 required for the enantioselective
cyclisation was prepared via a one-pot/two-step reaction involving
the in situ preparation of the iodobenzoic acid derived acid
chloride followed by a Friedel-Crafts acylation. This afforded
compound 10 in quantitative yield on a 15 g scale (35 mmol),
without the need for column chromatography. The palladium-
catalysed C-H activation functionalisation/cyclisation procedure,
shown in Scheme 3, allowed for the preparation of both
enantiomers of the planar chiral ketone, 11, in quantitative yield
with >99% ee by simply selecting the required hand of BINAP.
This synthesis is based on work from the groups of You and Gu
for the preparation of the enantioenriched ketones (R)-11 and (S)-
11; You noted that these conditions result in a reduction of ee
when the scale was increased to 1 g.[38,39] Minor modifications to
their methodology enabled the scale up of the reaction to 6 g (19
mmol) while simultaneously increasing the ee from 97% (as
reported by You) to 99%; in line with the procedure previously
described by us,[37] there is, no need for the use of column
chromatography.
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HO
step, a criterion not satisfied in these ferroceno[2,3]indene
derivatives. Indeed, the oxidation of 7d, lacking a labile proton β
to the ferrocenyl group, with silver oxide in acetone afforded only
unreacted starting compounds. Its oxidation under comparatively
mild (i.e., biologically relevant) oxidation conditions has also been
performed in the presence of HRP and H2O2, yet still only the
unreacted 7d was observed. This result parallels the case of the
ferrociphenol 12, in which the ethyl group was replaced by a
phenyl (Figure 6), thereby lacking an abstractable proton.[45]
Fe
Fe
Fe
O
O
NMe2
O
Me2N
17%a
NMe2
7%b
26%a
7a
(R)-
7b
(R)-
7a
(S)-
HO
OH
OH
Fe
Fe
32%b
7c
41%b
7c
(R)-
Fe
(S)-
OH
HO
12
Figure 6. Ferrociphenol 12, in which the ethyl group was replaced by a phenyl.
Fe
Fe
OH
HO
Biological studies
30%b
7d
(R)-
22%b
7d
(S)-
Table 1 lists the IC50 values for all new compounds against
the MCF-7 (ER+) and MDA-MB-231 (ER-) cell lines. Considering first
the ferrocifens (R)-7a and (S)-7a that are derived from the
ferrocenoindenones (R)-11 and (S)-11, respectively, their McMurry
coupled products are formed as 50/50 E/Z mixtures, as revealed by
Figure 5. Isolated yields of novel ferrocifens. (a) Yield after McMurry coupling.
(b) Yield after McMurry coupling and deprotection. Note: (S)-7b was accessed
in ca. 5% yield and proved difficult to purify in sufficient quantities for biological
evaluation.
1
the intensities of the H NMR spectral resonances of the C5H5 rings.
Thus, the E-(R)-7a and E-(S)-7a isomers are enantiomeric, as are
their Z-(R)-7a and Z-(S)-7a counterparts.
Upon synthesizing these compounds, it was immediately
apparent from their 1H and 13C NMR spectra that compounds 7a,
7b and 7c were each produced as a 1:1 mixture of geometric
(E/Z) isomers that were inseparable by column chromatography.
Nevertheless, our current understanding of the mechanism of
action of 4-hydroxyferrocifens suggests that only the isomer in
which the 4-hydroxyphenyl group is trans to the ferrocene moiety
will affect any significant QM-mediated bioactivity.[17,18,42] In
addition, it is recognized that interconversion of the E/Z occurs in
vivo so there is no benefit to attempt to separate these geometric
isomers.[1] However, the 4,4'-dihydroxy derivative 7d, obviously
does not possess this type of isomerism and precludes the E/Z
ratio from having an impact on the activity of the compound.
Table 1. The IC50 values of chiral ferrocifen compounds on MCF-7 (ER+) and
MDA-MB-231 (ER-) breast cancer cells
IC50 (μM)
MCF-7
MDA-MB-231
Compound
2b
3, n=3
5, n=1, R=OH
10
0.9
0.8
0.6
0.5
--
2.7 ± 0.1
9.0 ± 1.0
8.8 ± 0.4
5.9 ± 1.1
11.5 ± 0.5
16.1 ± 2.4
14.1 ± 1.0
4.2 ± 0.5
7.1 ± 0.5
--
(R)-7a
(S)-7a
(R)-7b
(R)-7c
(S)-7c
(R)-7d
(S)-7d
6.7 ± 0.7
5.2 ± 0.1
2.7 ± 0.7
16.0 ± 0.3
12.8 ± 1.7
6.3 ± 0.1
5.5 ± 2.0
Scheme 5. Stepwise mechanism of quinone methide formation.
Conversion of a ferrociphenol or ferrocifen into a QM requires the
removal of two hydrogens, a process now known to proceed in a
stepwise manner by sequential loss of electrons and protons
(Scheme 5).[43,44] We note in particular the requirement that the
system possesses an available abstractable proton in the final
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Since these molecules all possess the dimethylaminoethoxy
basic side-chain, they would be expected to show antiproliferative
behaviour against an ER+ cell line, such as MCF-7, and they do.
Of these, the ferrocifens of the S-series exhibit slightly better
activity. As both (Sp)- and (Rp)-7a are present in 50/50 E/Z
mixtures, any differences in IC50 necessarily arise from the
influence of planar chirality. Interestingly, these molecules
When incubated with breast cancer cells, ferrocifens
initiate a sequence of Fenton-type reactions[46] thus generating
ROS. [2] in particular hydroxyl radicals, which are highly genotoxic.
The cell can respond in a number of ways, such as by abstraction
of a hydrogen from a cysteine thiol moiety in thioredoxin, thus
forming water and a disulfide by intramolecular coupling of thiol
radicals. Regeneration of the dithiol unit requires the presence of
thioredoxin reductase but, if the ferrocifen forms a QM, the
selenocysteine therein readily undergoes Michael addition, thus
mitigating the cell’s ability to counteract the ROS. In sum, in the
absence of a QM, the cytotoxicity of ferroceno[2,3]indene
derivatives should result from the combined effects of the ROS
generation of the ferrocenyl unit and the estrogenic/anti-
estrogenic properties of the tamoxifen-type motif.
bearing
a
dimethylaminoethoxy basic side-chain exhibit
enhanced activity against the ER+ cells, but are noticeably worse
in the ER- case, especially in the case of E/Z-(R)-7b. Its IC50 value
decreases 5-fold on ER+ cells compared with that on ER- cells.
We have proposed this potent cytotoxicity on ER+ cells results
from the anti-estrogenic effect previously observed for
hydroxytamoxifen, 2b, and the hydroxyferrocifen 3 [20]. Indeed,
the effect of the new complexes on the growth of MCF-7 hormone-
dependent cells was then studied and E/Z-(R)-7b was observed
to show similar anti-estrogenic behaviour to that of Fc-OH-Tam
(Figure 7).
Finally, for comparison, in Table 2 we note the perhaps
surprisingly low IC50 values of the ferrocidiphenol, 7d, and the
ferrocifen, 7b, (even though they cannot form QMs), and the
bicyclo complex, 5. In all three cases, the (E)-ferrocenyl-ene-p-
phenol framework is readily accessible, but we emphasise that 5
was prepared only in the racemic form and so, unlike in the
present study, no experimental investigation of chiral
discrimination was possible. We note, however, that in an
exhaustive molecular modelling/energy minimisation study,
whereby each enantiomer of the polycyclic ferrocidiphenol 5 was
allowed to dock with ERα and ERß, binding of the (S)-5
enantiomer was clearly superior to that of its (R)-5 counterpart.[28]
Table 2. A comparison of ferrocidiphenol (R)-7d, ferrocifen (R)-7b and racemic
ferrocidiphenol 5.
(R)-7d
(R)-7b
rac-5
6.3 ±
0.1
MCF-7
2.7 ± 0.7
--
IC50
Figure 7. Antiproliferative and proliferative effects of chiral ferrocifen
compounds (1 μM) on MCF-7 cells after 5 days culture. E2 = estradiol, C =
control.
(μM)
MDA-MB-
231
4.2 ±
0.5
11.5 ±
0.5
2.7 ±
0.1
A
genuine comparison of the behaviour of pure
enantiomers is revealed by the ferrocidiphenols (R)-7d and (S)-7d.
Here, the (R)-enantiomer is somewhat better than its (S)-
counterpart against the ER- cell line, but the situation is less clear
in the ER+ case because of the larger error limits for the favoured
(S)-enantiomer, despite repeated assays. Finally, the IC50 values
for the ferrociphenols (R)-7c and (S)-7c (both as 50/50 E/Z
mixtures) are markedly higher than were found for the ferrocifens
7a and 7b, and the ferrocidiphenols 7d. Significantly, monophenol
7c, which exists as a 50:50 mixture of E and Z isomers, exhibits
IC50 values at least twice that of diphenol 7d. This result parallels
the observed 2-fold difference in cytotoxicity between the
ferrociphenol, 2a, and its corresponding diphenol, 2b; in the latter
case an E-phenol substituent is always available for QM
formation.[2] After five days culture on MCF-7 cells, ferrociphenols
7c and 7d show estrogenic behaviour similar to that of the natural
hormone estradiol. Meanwhile, as shown above, the oxidation of
Conclusion
The key step in the preparation of these enantiopure ferrocifens
and ferrociphenols is the efficient preparation of the chiral
ferrocenyl ketone 11 in >99% ee and quantitative yield using a
palladium-catalysed
intramolecular
direct
C-H
bond
activation/cyclisation. It is apparent from previous reports that
chiral ferrocifens such as 5 have not been prepared even in an
enantioenriched form due to the relative inaccessibility of a single
enantiomer of the ferrocenyl ketones because of the extensive
time-consuming preparations and purifications.[28] Indeed, it is the
robust and rapid synthesis of our enantiopure ketones that
enables the facile synthesis of the first enantiopure ferrocifens for
biological evaluation.
The bioactivity of ferrociphenols and ferrocifens derived
from enantiomerically pure (S)- and (R)-ferroceno[2,3]indanones
against breast cancer cell lines is somewhat reduced from that of
their ferrocenyl counterparts, but there is chiral discrimination.
ferroceno[2,3]indene
derivatives
cannot
produce
the
corresponding QM, hence the observed anti-proliferative effect
can be attributed only to a cytotoxic effect potentially induced by
the ferrocenyl unit, as in the case of compound 10.[45]
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(S)-Ferroceno[2,3-a]inden-1-one (S)-11. (o-Iodobenzoyl)ferrocene 10
(1.66 g, 4.0 mmol) was added to a dry, nitrogen-flushed, 50 mL Schlenk
flask equipped with a magnetic stirring bar. Cs2CO3 (2.60 g, 8.0 mmol),
Pd(OAc)2 (18.0 mg, 0.08 mmol, 2.0 mol%), (S)-BINAP (106 mg, 0.16 mmol,
4.0 mol%) and pivalic acid (134 mg, 0.60 mmol, 30 mol%) were then added
sequentially followed by toluene (16 mL, 0.25 M) and stirring was
commenced. The Schlenk flask was then immediately placed in an oil bath
set to 100 ºC and the conversion monitored by SFC. After 16 h the reaction
had reached 100% conversion and was allowed to cool to RT before
The IC50 values reveal that, in general, the molecules possessing
the (S)-configuration perform better against the ER+ cell line,
MCF-7, but the result is less clear in the ER- case. It is noticeable,
however, that, even though complete transformation to a neutral
QM is not possible because of the lack of an abstractable proton,
these systems are bioactive.
filtration through
a pad of Celite 545® with CH2Cl2 followed by
Experimental Section
concentration in vacuo to provide the cyclized ferrocene (1.15 g, 99% yield,
99% ee) as a dark purple solid. 1H NMR (400 MHz, CDCl3) δ 7.49 (d, J =
7.6 Hz, 1H), 7.27 (m, 1H), 7.12 (m, 2H), 4.97 (d, J = 2.4 Hz, 1H), 4.86 (m,
2H), 4.12 (s, 5H); TLC (pentane:Et2O, 5:3), Rf: 0.40 (UV, Vis, purple). SFC
analysis (CHIRALPAK IB, scCO2/iPrOH, 99/1 to 60/40 over 7 min, 3
mL/min) tR = 3.85 min (S) and tR = 4.08 min (R). All other characterization
is in agreement with reported literature data. [38,39]
General Information: Unless otherwise noted, all commercial reagents
were used as received without further purification. Planar chiral ketones
(S)-9 and (R)-9 were prepared by a modified procedure based on those
originally reported by the groups of You and Gu.[37,38] Substituted
benzophenones 4-(dimethylaminoethoxy)benzophenone,[47] 4,4’-(di-tert-
butyldimethylsilyloxy)benzophenone[48]
and
(4-((tert-
butyldimethylsilyl)oxy)phenyl)(phenyl)methanone[49] were prepared by
known literature procedures. Standard Schlenk line techniques were
employed for moisture sensitive reactions. Column chromatography was
performed on Davisil LC60A 40-63 micron silica gel. Thin-layer
chromatography (TLC) was performed on aluminium-backed sheets
purchased from Merck pre-coated with silica gel 60 F254. 1H NMR spectra
were recorded on Varian-Inova spectrometers (300, 400, 500 and
600 MHz) using tetramethylsilane as an internal standard. 13C NMR
spectra were recorded on 400 MHz, 500 and 600 MHz Varian-Inova
spectrometers (101, 126 and 151 MHz) using tetramethylsilane as an
internal standard and were proton decoupled. HRMS were measured on a
Micromass/Waters LCT mass spectrometer. Supercritical fluid
chromatography (SFC) was performed on a Waters Acquity UPC2®
instrument with Chiralpak® IA3, IB3, IC3 and ID3 columns. Optical rotation
measurements were recorded using a Schmidt-Haensch Unipol L2000
polarimeter at 589 nm and are quoted in units of deg dm-1 cm3 g-1
(concentration c is given in g/100 mL).
Example procedure for McMurry Coupling of TBS protected
benzophenones with ferrocenyl ketone (S)-11:
(S)-1-[1,1-di(4-hydroxyphenyl)methyliden]ferroceno[2,3-a]indene,
(S)-7d. Zn dust (10 µ powder, 588 mg, 9.0 mmol) was added to a dry N2
flushed 50 mL Schlenk flash, suspended in THF (15 mL) before being
cooled to 0 ºC. TiCl4 (0.45 mL, 4.5 mmol) was then added dropwise before
removing the Schlenk flask from the ice bath and placing it in an oil bath
heated to 70 ºC. After 1 h of heating the solution was cooled to 0 ºC and
pyridine (0.19 mL, 2.34 mmol) was added and left to stir for 10 min. During
this time a 1:3 mixture of ketones (S)-11 (259 mg, 0.9 mmol) and 4,4’-(di-
tert-butyldimethylsilyloxy)benzophenone (1195 mg, 2.7 mmol) in THF (15
mL) was prepared and added slowly to the reaction mixture before being
heated to 70 ºC and monitored by TLC for the disappearance of (S)-11.
After 2 h the reaction was cooled to RT and quenched by adding 2.0M
K2CO3 (~10 mL), this was diluted with CH2Cl2 (30 mL) and the organic and
aqueous layers were separated. The aqueous layer was back-extracted
with CH2Cl2 (3 x 15 mL), the combined organic layers were dried (MgSO4),
filtered and concentrated in vacuo. The crude mixture was purified by silica
gel chromatography (pentane:Et2O, 99:1) to provide an inseperable
mixture of the heterocoupled product and the homocoupled bis(4-((tert-
butyldimethylsilyl)oxy)phenyl)methanone product. This mixture was
deprotected with TBAF (1.0M solution in THF, 5.0 mL, 5.0 mmol) by stirring
at RT for 5 min before being diluted with CH2Cl2 (10 mL) and H2O (10 mL)
and the organic and aqueous layers were separated. The aqueous layer
was back-extracted with CH2Cl2 (10 mL), the combined/ organic layers
were dried (MgSO4), filtered and concentrated in vacuo. This mixture was
then purified by silica gel chromatography (CH2Cl2:Et2O, 95:5) to provide
(o-Iodobenzoyl)ferrocene (10). 2-Iodobenzoic acid (8.65 g, 35.0 mmol)
was added to a dry, nitrogen-flushed, 250 mL Schlenk tube equipped with
a large magnetic stirring bar and nitrogen/vacuum inlet. CH2Cl2 (50 mL)
was added along with 1 drop of DMF to form a white suspension and
stirring was commenced. Oxalyl chloride (3.9 mL, 45.5 mmol) was added
to this suspension over 2 min at 0 ºC. The reaction was stirred at RT for 1
h until the suspension had turned to a clear solution and the evolution of
gas had ceased. The Schlenk tube was then submerged in a water bath
at RT and the solvent and remaining oxalyl chloride removed using a high-
vacuum and a liquid N2 cooled collection flask. The crude acid chloride
was dried under vacuum at RT for a further 1 h before being dissolved in
CH2Cl2 (40 mL) and ferrocene (6.53 g, 35.0 mmol) was then added along
with CH2Cl2 (20 mL). This solution was cooled to 0 ºC before addition of
AlCl3 (4.65 g, 35.0 mmol) in 4 equal portions over 5 min and left to stir for
a further 10 min while being warmed to RT. The reaction was quenched
by pouring the mixture into 100 mL of ice water and the layers were
separated before back extracting the aqueous layer with CH2Cl2 (3 x
30 mL). The organic layers were combined and then washed with a 10%
D
the heterocoupled product (91 mg, 22% yield) as a red oil/gum: [α]20 = -
1923 (c = 0.03, CHCl3); IR (ATR) νmax 3301, 3028, 2850, 1604 cm-1; 1H
NMR (500 MHz, CDCl3) δ 7.37 (d, J = 8.0 Hz, 2H), 7.33 (d, J = 7.4 Hz, 2H),
7.26 – 7.20 (m, 1H), 7.07 (t, J = 7.4 Hz, 1H), 6.88 (d, J = 7.9 Hz, 2H), 6.87
– 6.79 (m, 3H), 6.69 (d, J = 7.9 Hz, 1H), 4.84 (s, 2H), 4.62 (d, J = 2.3 Hz,
1H), 4.21 (t, J = 2.3 Hz, 1H), 3.94 (s, 5H), 3.76 (d, J = 2.3 Hz, 1H); 13C
NMR (126 MHz, CDCl3) δ 155.3, 155.1, 142.7, 141.5, 137.6, 136.8, 135.4,
134.3, 131.6, 131.4, 127.4, 125.0, 124.3, 120.0, 115.6, 115.3, 89.9, 89.3,
71.2, 70.8, 64.4, 60.4; HRMS: (ESI-TOF) calculated for C30H22O2Fe [M]+
470.0969, found 470.0992; TLC (CH2Cl2:Et2O, 9:1), Rf: 0.55 (UV, Vis, Red).
NaOH solution (3
x 30 mL) and dried with MgSO4 before being
concentrated in vacuo. The crude material was dissolved in CH2Cl2 (30
mL) and filtered through a pad of Celite 545® with CH2Cl2 before being
concentrated in vacuo. This provided the substituted ferrocene (10.0 g,
99%) as a red solid: 1H NMR (400 MHz, CDCl3) δ 7.92 (d, J = 7.9 Hz, 1H),
7.56 – 7.47 (m, 1H), 7.43 (t, J = 7.4 Hz, 1H), 7.15 (t, J = 7.6 Hz, 1H), 4.73
(s, 2H), 4.60 (s, 2H), 4.30 (s, 5H). All other characterization is in agreement
with reported literature data.[38,39]
(R)-1-[1,1-di(4-hydroxyphenyl)methyliden]ferroceno[2,3-a]indene,
(R)-7d. Using the same procedure as for (S)-7d above, employing (R)-7d
to provide the heterocoupled product (58 mg, 21% yield) as a red oil/gum.
Matching analytical data obtained for the opposite enantiomer (S)-7d:
[α]20D = +2081 (c = 0.04, CHCl3).
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FULL PAPER
(S)-1-[(1-(4-hydroxyphenyl)-1-phenyl)methyliden]ferroceno[2,3-
a]indene, (S)-7c. A 1:3 mixture of (S)-11 (172 mg, 0.6 mmol) and the
required benzophenone (562 mg, 1.8 mmol) was used, following the same
procedure as for (S)-7d above to provide the heterocoupled product (86
mg, 32% yield) as a mixture of E/Z isomers as a red solid: Mp 46 °C with
7.48 (d, J = 7.4 Hz, 1H), 7.45 – 7.30 (m, 7H), 7.07 (qd, J = 7.6, 1.1 Hz, 1H),
6.97 (d, J = 8.82 Hz, 1H), 6.93 (d, J = 8.31 Hz, 1H), 6.83 (td, J = 7.7, 1.3
Hz, 0.5H), 6.78 (td, J = 7.7, 1.2 Hz, 0.5H), 6.72 (dt, J = 7.8, 0.9 Hz, 0.5H),
6.54 (dt, J = 7.9, 0.9 Hz, 0.5H), 4.62 (dd, J = 2.3, 0.8 Hz, 0.5H), 4.60 (dd,
J = 2.3, 0.8 Hz, 0.5H), 4.21 (t, J = 2.3 Hz, 0.5H), 4.17 (t, J = 2.3 Hz, 0.5H),
4.13 (dt, J = 11.1, 5.7 Hz, 2H), 3.95 (s, 2.5H), 3.94 (s, 2.5H), 3.76 (dd, J =
2.3, 0.8 Hz, 0.5H), 3.57 (dd, J = 2.3, 0.8 Hz, 0.5H), 2.78 (q, J = 6.1 Hz, 2H),
2.38 (s, 3H), 2.36 (s, 3H); 13C NMR (126 MHz, CDCl3) δ 158.6, 158.4,
144.2, 142.9, 142.6, 141.50, 141.46, 137.93, 137.90, 136.5, 135.1, 134.8,
134.7, 131.1, 130.9, 129.9, 129.7, 128.7, 128.4, 127.7, 127.51, 127.50,
127.4, 125.1, 125.0, 124.42, 124.37, 120.0, 119.9, 119.8, 114.7, 114.4,
89.8, 89.7, 89.0, 88.9, 71.19, 70.84, 70.83, 66.2, 66.1, 64.6, 64.5, 60.41,
60.38, 58.55, 58.52, 46.1. HRMS: (ESI-TOF) calculated for C34H32NOFe
[M+H]+ 526.1833, found 526.1844; TLC (CH2Cl2:MeOH, 9:1), Rf: 0.55 (UV,
Vis, Red).
D
decomposition (CH2Cl2); [α]20 = -2279 (c = 0.086, CHCl3); IR (ATR) νmax
3508, 3052, 3013, 1605 cm-1; 1H NMR (500 MHz, CDCl3) δ 7.54 – 7.31 (m,
7.5H), 7.16 – 7.02 (m, 1H), 6.95 – 6.53 (m, 4.5H), 5.08 (s, 1H), 4.66 (d, J
= 2.3 Hz, 0.5H), 4.63 (d, J = 2.3 Hz, 0.5H), 4.25 (t, J = 2.2 Hz, 0.5H), 4.21
(t, J = 2.3 Hz, 0.5H), 3.98 (s, 2.5H), 3.97 (s, 2.5H), 3.82 (d, J = 2.3 Hz,
0.5H), 3.61 (d, J = 2.3 Hz, 0.5H). 13C NMR (126 MHz, CDCl3) δ 158.02,
157.87, 156.66, 156.39, 142.91, 142.68, 141.22, 141.13, 136.76, 135.58,
135.44, 134.17, 133.56, 131.39, 131.27, 131.23, 131.09, 126.99, 124.92,
124.83, 124.16, 124.13, 119.78, 119.72, 115.96, 115.61, 113.78, 89.60,
89.58, 89.39, 89.35, 70.96, 70.91, 70.54, 70.46, 64.41, 64.38, 64.27, 64.23,
60.03, 58.12, 58.10, 45.19, 45.16. HRMS: (ESI-TOF) calculated for
C30H22OFe [M]+ 454.1020, found 454.1027; TLC (CH2Cl2, neat), Rf: 0.40
(UV, Vis, Red).
(S)-1-[(1-(4-dimethylaminoethoxyphenyl)-1-
phenyl)methyliden]ferroceno[2,3-a]indene, (S)-7a. Same procedure as
for (R)-7a above, (S)-7a to provide the heterocoupled product (24 mg, 7%
yield) as a red oil/gum. Matching analytical data obtained for the opposite
enantiomer (R)-7a: [α]20D = -2389 (c = 0.025, CHCl3).
(R)-1-[(1-(4-hydroxyphenyl)-1-phenyl)methyliden]ferroceno[2,3-
a]indene, (R)-7c. Using the same procedure as for (S)-7c above, (R)-7c
to provide the heterocoupled product (113 mg, 41% yield) as a red solid.
Matching analytical data obtained for the opposite enantiomer (S)-7c:
[α]20D = +2133 (c = 0.080, CHCl3).
Characterization data and NMR spectra for all new compounds are
available as supplementary data (PDF)
(R)-1-[(1-(4-dimethylaminoethoxyphenyl)-1-(4-
Biological methods. Materials. Stock solutions (1 x 10-3 M) of the
ferrocenyl complexes to be tested were prepared in DMSO and were kept
at 4°C, serial dilutions in DMSO were prepared just prior to use. A stock
solution (1 x 10-3 M) of estradiol was prepared in ethanol. (Dulbecco’s
modified eagle medium (DMEM) was purchased from Gibco BRL, fetal calf
serum from Dutscher, Brumath, France, glutamine, E2 and protamine
sulfate were from Sigma.) MCF-7 and MDA-MB-231 cells were from the
Human Tumor Cell Bank.
hydroxyphenyl)methyliden]ferroceno[2,3-a]indene, (R)-7b
A
2:1
mixture of (R)-11 (290 mg, 1 mmol) and the required benzophenone (210
mg, 0.5 mmol) was used, following the same procedure as for (S)-7d
above to provide the heterocoupled product (24 mg, 7% yield) as a mixture
D
of E/Z isomers as a red solid. Mp 102-108 oC; [α]20 = -3084 (c = 0.05,
CH2Cl2); 1H NMR (400 MHz, CDCl3) δ 7.38-7.29 (m, 3H), 7.20 (s, 2H), 7.05
(t, J = 7.4 Hz, 1H), 6.93 – 6.78 (m, 3H), 6.77-6.61 (m, 3H), 4.60 (t, J = 2.0
Hz, 1H), 4.18 – 4.09 (m, 3H), 3.93 (s, 2.5H), 3.92 (s, 2.5H), 3.80 (d, J = 2.4
Hz, 0.5H) 3.77 (d, J = 2.4 Hz, 0.5H), 2.91 (q, J = 6.0 Hz, 2H), 2.51 (s, 3H)
2.49 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 158.02, 157.87, 156.66, 156.39,
142.91, 142.68, 141.22, 141.13, 136.76, 135.58, 135.44, 134.17, 133.56,
131.39, 131.27, 131.23, 131.09, 126.99, 124.92, 124.83, 124.16, 124.13,
119.78, 119.72, 115.96, 115.61, 113.78, 89.60, 89.58, 89.39, 89.35, 70.96,
70.91, 70.54, 70.46, 64.41, 64.38, 64.27, 64.23, 60.03, 58.12, 58.10, 45.19,
45.16. IR (ATR) 3052, 2927, 1604, 1508 cm-1. HRMS: (ESI-TOF)
calculated for C34H31FeNO2 [M]+ 542.1782, found 542.1758.
Culture Conditions. Cells were maintained in monolayer culture in DMEM
with phenol red/Glutamax I, supplemented with 9% of decomplemented
fetal calf serum and 0.9% kanamycine, at 37°C in a 5% CO2 air humidified
incubator. For proliferation assays, cells were plated in 24-well sterile
plates at a density of 1.1.104 cells for MDA-MB-231 and of 3.104 cells for
MCF-7 in 1 mL of DMEM without phenol red, supplemented with 9% of
fetal calf serum desteroided on dextran charcoal, 0.9% Glutamax I and
0.9% kanamycine, and were incubated for 24 h. The following day (D0), 1
mL of the same medium containing the compounds to be tested diluted in
DMSO, was added to the plates (final volumes of DMSO: 0.1%). After
three days (D3), the incubation medium was removed and 2 mL of fresh
medium containing the compounds was added. At different days (D4, D5),
the protein content of each well was quantified by methylene blue staining
as follows. Cell monolayers were fixed and stained for 1h in methanol with
methylene blue (2.5 mg/mL), and then washed thoroughly with water. Two
milliliters of HCl (0.1 M) was then added, and the plate was incubated for
1h at 37°C. Then the absorbance of each well was measured at 655 nm
with a Biorad spectrophotometer (microplate reader). The results are
expressed as the percentage of proteins versus the control. Experiments
were performed at least in duplicate.
(R)-1-[(1-(4-dimethylaminoethoxyphenyl)-1-
phenyl)methyliden]ferroceno[2,3-a]indene, (R)-7a. Zn dust (10µ
powder, 400mg, 6.12 mmol) was added to a dry, N2 flushed 50 mL Schlenk
flask equipped with a magnetic stirring bar and suspended in THF (10 mL)
before being cooled to 0 ºC. TiCl4 (0.33 mL, 3.0 mmol) was then added
dropwise before removing the Schlenk flask from the ice bath and placing
i in an oil bath heated to 70 ºC. After 1 h of heating the solution was cooled
to 0 ºC and pyridine (0.13 mL, 1.56 mmol) was added and left to stir for 10
min. During this time a 1:2 mixture of ketones (S)-11 (172 mg, 0.6 mmol)
and 4-(dimethylaminoethoxy)benzophenone (323 mg, 1.2 mmol) in THF
(10 mL) was prepared and added slowly to the reaction mixture before
being heated to 70 ºC and monitored by TLC for the disappearance of (S)-
11. After 30 min the reaction was cooled to RT and quenched by adding
2.0 M K2CO3 (~5 mL), this was diluted with CH2Cl2 (20 mL) and the organic
and aqueous layers were separated. The aqueous layer was back-
extracted with CH2Cl2 (3 x 15 mL), the combined organic layers were dried
(MgSO4), filtered and concentrated in vacuo. The crude mixture was
purified by silica gel chromatography (CH2Cl2:MeOH, 100:0 to 95:5) to
provide the heterocoupled product (81 mg, 26% yield) as a mixture of E/Z
Acknowledgements
This publication has emanated from research conducted (LC) with
the financial support the Synthesis and Solid State
Pharmaceutical Centre, funded by Science Foundation Ireland
D
isomers as a red solid: Mp 50-54 °C (CH2Cl2); [α]20 = +2420 (c = 0.025,
CHCl3); IR (ATR) 3052, 2930, 1603 cm-1; 1H NMR (600 MHz, CDCl3) δ
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10.1002/cbic.202000311
ChemBioChem
FULL PAPER
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Keywords: ferrocifen • anti-tumor agents • enantioselective
synthesis • chirality • bioorganometallics
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