Aerobic iron-based cross-dehydrogenative coupling enables efficient diversity-oriented synthesis of coumestrol-based selective estrogen receptor modulators

Article abstract of DOI:10.1002/chem.201300389

An iron-based cross-dehydrogenative coupling (CDC) approach was applied for the diversity-oriented synthesis of coumestrol-based selective estrogen receptor modulators (SERMs), representing the first application of CDC chemistry in natural product synthesis. The first stage of the two-step synthesis of coumestrol involved a modified aerobic oxidative cross-coupling between ethyl 2-(2,4-dimethoxybenzoyl)acetate and 3-methoxyphenol, with FeCl₃ (10 mol %) as the catalyst. The benzofuran coupling product was then subjected to sequential deprotection and lactonization steps, affording the natural product in 59 % overall yield. Based on this new methodology other coumestrol analogues were prepared, and their effects on the proliferation of the estrogen receptor (ER)-dependent MCF-7 and of the ER-independent MDA-MB-231 breast cancer cells were tested. As a result, new types of estrogen receptor ligands having an acetamide group instead of the 9-hydroxyl group of coumestrol were discovered. Both 9-acetamido-coumestrol and 8-acetamidocoumestrol were found more active than the natural product against estrogen-dependent MCF-7 breast cancer cells, with IC₅₀ values of 30 and 9 nM, respectively. Green medicinal chemistry: An iron-based cross-dehydrogenative coupling (CDC) approach was applied for the diversity-oriented synthesis of coumestrol-based selective estrogen receptor modulators (SERMs), representing the first application of CDC chemistry in natural product synthesis (see scheme; DCE=dichloroethane). Copyright

Full text of DOI:10.1002/chem.201300389

FULL PAPER
DOI: 10.1002/chem.201300389
Aerobic Iron-Based Cross-Dehydrogenative Coupling Enables Efficient
Diversity-Oriented Synthesis of Coumestrol-Based Selective Estrogen
Receptor Modulators
Umesh A. Kshirsagar,[a] Regev Parnes,[a] Hagit Goldshtein,[b] Rivka Ofir,[b, c]
Raz Zarivach,[d] and Doron Pappo*[a]
Abstract: An iron-based cross-dehy-
drogenative coupling (CDC) approach
was applied for the diversity-oriented
synthesis of coumestrol-based selective
as the catalyst. The benzofuran cou-
pling product was then subjected to se-
quential deprotection and lactonization
steps, affording the natural product in
59% overall yield. Based on this new
methodology other coumestrol ana-
logues were prepared, and their effects
on the proliferation of the estrogen re-
ceptor (ER)-dependent MCF-7 and of
the ER-independent MDA-MB-231
breast cancer cells were tested. As a
result, new types of estrogen receptor
ligands having an acetamide group in-
stead of the 9-hydroxyl group of cou-
mestrol were discovered. Both 9-acet-
amido-coumestrol and 8-acetamidocou-
mestrol were found more active than
the natural product against estrogen-
dependent MCF-7 breast cancer cells,
with IC50 values of 30 and 9 nm, respec-
tively.
estrogen
receptor
modulators
(SERMs), representing the first appli-
cation of CDC chemistry in natural
product synthesis. The first stage of the
two-step synthesis of coumestrol in-
volved a modified aerobic oxidative
cross-coupling between ethyl 2-(2,4-di-
Keywords: cross-coupling · iron ·
natural products · structure–activity
relationships · total synthesis
methoxybenzoyl)acetate
and
3-
methoxyphenol, with FeCl3 (10 mol%)
ACHTUNGTRENNUNG
Introduction
organic peroxide.[1] Since the pioneering work of Chao-Jun
Li,[2] many types of weak C H bonds have been activated
À
The cross-dehydrogenative coupling (CDC) reaction has
become a powerful synthetic tool for the formation of new
carbon–carbon bonds. Starting from two different C H
bonds, a new C C bond is formed through an oxidative cou-
pling process catalyzed by earth-abundant metals, such as
copper and iron, in the presence of an oxidant, usually an
under CDC conditions,[3] thereby enabling easy access to
many complex molecular structures.[4] Despite the fact that
iron and copper CDC chemistry can offer opportunities for
the synthesis of natural products in a practical manner and
in an environmental friendly way[5]—in keeping with the de-
mands of modern chemistry—the true value of these reac-
tions in target- and diversity-oriented syntheses has not
been examined.[5]
À
À
[a] Dr. U. A. Kshirsagar,+ R. Parnes,+ Dr. D. Pappo
Department of Chemistry
Oxidative cross-coupling reactions have garnered much
attention in recent years, because they offer rapid access to
late intermediates. Indeed, many exciting transformations
based on copper and iron oxidants have successfully been
applied in natural product synthesis,[6] but the downside of
most of these reactions is that they require supra-stoichio-
metric amounts of the metal oxidant.[1a] Of particular impor-
tance is the homodimerization of two phenol (or protected
phenol) units by a stoichiometric amount of iron oxidant—a
common protocol in organic chemistry[7] whose application
in natural product synthesis goes back to the work of
Barton.[8] However, oxidative cross-coupling reactions of
phenols by stoichiometric amount of iron oxidants suffer
from low efficiency as a result of poor chemo- and regiose-
lectivity,[9] which makes these reactions not particularly suit-
able for target-oriented synthesis.
Ben-Gurion University of the Negev
Beer-Sheva 84105 (Israel)
Fax : (+972)8-6428693
E-mail: pappod@bgu.ac.il
[b] H. Goldshtein, Dr. R. Ofir
Dead Sea & Arava Science Center
Ben-Gurion University of the Negev
Beer-Sheva 84105 (Israel)
[c] Dr. R. Ofir
Department of Microbiology & Immunology
Ben-Gurion University of the Negev
Beer-Sheva 84105 (Israel)
[d] Dr. R. Zarivach
Department of Life Sciences
Ben-Gurion University of the Negev
and the National Institute for Biotechnology
Ben-Gurion University of the Negev
Beer-Sheva 84105 (Israel)
[+] These Authors contributed equally to this work.
In contrast to the above reactions, any iron-based CDC
strategy that requires only catalytic amounts of the metal
salt offers opportunities for developing biomimetic coupling
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201300389.
Chem. Eur. J. 2013, 00, 0 – 0
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
&
1
&
ÞÞ
These are not the final page numbers!

reactions of simple phenols with various active CH atoms.
Indeed, a number of practical catalytic systems for the cou-
pling of 2-naphthol (3a) with sp2 and sp3 carbons have re-
cently been developed.[10] In 2009, the group of Zhiping Li
reported the formation of substituted benzofurans (such as
4, Scheme 1) through direct coupling of b-ketoesters such as
in human nutrition has thus been studied comprehensive-
ly.[14],[19]
In vitro studies found that coumestrol bind to estrogen re-
ceptors (ERs),[20] ERa and ERb. These two subtypes of the
receptor, which belong to the nuclear hormone family of in-
tracellular receptors, play essential roles not only in devel-
opment and maintenance of normal sexual and reproductive
function but also in the progression of cancer and other dis-
eases.[21] Importantly, whereas the natural estrogen, 17a-es-
tradiol (E2, Figure 1) binds to both ER subtypes with similar
Figure 1. The structure of coumestrol (1) and 17a-estradiol (E2).
Scheme 1. Iron-catalyzed oxidative coupling of phenols and b-ketoesters.
Reagents and conditions: FeCl3 (10 mol%), 1,10-phenanthroline
(5 mol%), DTEP (2.5 mmol), DCE, 708C
affinity, the phytoestrogen coumestrol (1, Figure 1) binds
with essentially the same affinity as E2 to ERb but with
lower affinity than that for the a-subtype.[22] The ability to
distinguish between the ER subtypes is of high value as it
greatly improves the side-effect profile of a drug. Indeed,
much effort is currently being invested in developing such
selective estrogen-receptor modulators (SERMs).[23–25]
Despite significant potential of coumestrol as a drug, the
absence of an efficient synthetic strategy that can provide
the natural product and its unnatural analogues in sufficient
amounts for biology studies has frustrated any further devel-
opments. Several total syntheses of coumestrol have been
reported (see Scheme 2),[26] but these usually involve multi-
step syntheses, which afford only small quantities of the nat-
ural product, leaving the production problem unsolved.[26a,b,d]
The synthesis of other members of the coumestan family has
also been documented,[17b,27] and recently an efficient ap-
proach for the synthesis of coumestans was developed by
Du and Zhao.[28]
2a with phenol derivatives, with FeCl3·ACHTUNTRGNEUNG(H2O)6 (10 mol%)
and di-tert-butyl peroxide (DTBP; 2 equiv) serving as the
oxidant (in dichloroethane (DCE) at 1008C).[11] Under these
reaction conditions, annulation and dehydration steps take
place.[11] Although this reaction proved to be successful for a
variety of phenols (mainly phenols bearing alkyl substitu-
tions), it required a large excess of the phenol partner
(3 equiv) and it suffered from moderate chemoselectivity as
a result of Friedel–Craft side reactions.
Recently, our group developed a method for coupling
electron-rich phenol and naphthol derivatives with cyclic
and acyclic a-substituted-b-ketoesters (FeCl3: 10 mol%,
1,10-phenanthroline: 5 mol%, DTBP (2.5 equiv), DCE;
708C, Scheme 1).[12] As a result of this transformation, a new
quaternary carbon bond is formed within a polycyclic hemi-
acetal or polycyclic spirolactone architecture such as 5,
which contains the polycyclic core of lachnanthospirone nat-
ural product.[12] In our method, the introduction of a ligand
was found to dramatically improve the chemoselectivity and
the efficiency of the reactions and to reduce the formation
of Friedel–Crafts by-products. Our conditions were also ap-
plied for the synthesis of benzofuran 4 from ethyl 2-benzyl-
ACHTUNGTRENNUNGoxyacetate (2a) and 2-naphthol (3a), giving an improved
68% yield.[12]
Coumestrol is the most important member of the coume-
stan family of phytochemicals[13] containing a 6H-benzofuro-
ACHTUNGTRENNUNG
[3,2-c][1]benzopyran-6-one skeleton.[14] The group comprises
hundreds of molecules with different oxygenation patterns.
The coumestans are found in a variety of plant species that
are commonly used in traditional medicine. They exhibit a
range of biological activities, including estrogenic,[14,15] anti-
bacterial, antifungal, and snake anti-venom[16] activities and
phytoalexine effects.[17] Among the coumestans, coumestrol
1 is an important dietary ingredient that is found not only in
forage plants, but also in cabbages and soybeans;[18] its role
Scheme 2. Selected total syntheses of coumestrol (1).
&
2
&
www.chemeurj.org
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 0000, 00, 0 – 0
ÝÝ
These are not the final page numbers!

Aerobic Iron-Based Cross-Dehydrogenative Coupling
FULL PAPER
Here, we report the first application of iron-based CDC
chemistry in the context of natural product synthesis. A di-
versity-oriented synthesis for a library of coumestrol-based
SERMs was developed utilizing a modified aerobic iron-cat-
alyzed coupling reaction of b-ketoesters and phenols. The
work included a gram-scale total synthesis of coumestrol
itself. The estrogenicity of the different coumestrol ana-
logues that were synthesized was evaluated by testing their
effects on the proliferation of two breast cancer cell lines,
the ER-dependent MCF-7 line and the ER-independent
MDA-MB-231 line. It was found that new coumestrol ana-
logues, having either an 8- or a 9-NHAc group instead of
the 9-OH group of coumestrol, exhibited high potency
against the MCF-7 cell line.
Scheme 4. Total synthesis of coumestrol. Conditions: a) FeCl3 (10 mol%),
2,2’-bipyridine (5 mol%), tBuOOtBu (2.5 equiv), DCE, 708C, 8 h, 61 %
yield (gram-scale yield); b) BBr3 (1m in CH2Cl2), CH2Cl2, 18 h; then
EtOH, 808C, 4 h, 97% yield.
Results and Discussion
The synthetic work in this project was started by developing
an efficient entry to the coumestan family. Our retrosynthet-
ic analysis of coumestrol is illustrated in Scheme 3. The
demonstrate the possibility of scaling up this method, a
gram-scale (10 mmol) synthesis of coumestrol was success-
fully accomplished; over 1.6 g of the natural product was
prepared (in 59% overall yield) by an undergraduate stu-
dent in as little as three days.
After succeeding in solving the production problem of
coumestrol, we applied our protocol to the synthesis of
other natural members of the coumestan family, namely,
coumestan (20) and 8,9-dihydroxycoumestrol (22)[31] (en-
tries 1 and 3, Table 2). Thus, the coupling reaction between
Table 1. Optimization of the CDC reaction of b-ketoester 2c and phenol
3c under oxygen and aerobic conditions.[a]
Scheme 3. General retrosynthetic analysis of coumestans
strategy was based on our prediction that the coumestan
structural motif could be synthesized from the correspond-
ing benzofurans 6 through sequential demethylation and lac-
tonization steps, with the latter may be prepared by using
iron-catalyzed CDC reactions between ethyl 2-benzoylace-
tate 2c and 3-methoxyphenol (3c).
Entry
Conditions
Yield[b] [%]
1
2
3
4
5
FeCl3 (10 mol%), NHPI (5 mol%), O2
FeCl3 (10 mol%), NHPI (20 mol%), O2
FeCl3 (10 mol%), O2
61
53
63
FeCl3 (10 mol%), 2,2’-bipyridine (5 mol%), O2
A
FeCl3 (10 mol%), atmospheric air[d]
52
Our two-step total synthesis of coumestrol (1) started
with the iron-based cross-coupling reaction of ethyl 2-(2,4-
dimethoxybenzoyl)acetate (2c, 1 equiv) and 3-methoxyphe-
nol (3c, 1.1 equiv), both commercially available,[29] by using
FeCl3 (10 mol%) and 2,2’-bipyridine (5 mol%) as addi-
tives[30] and DTBP (2.5 equiv) as the oxidant, in DCE (0.5m)
at 708C for 8 h (Scheme 4). Under these conditions, benzo-
furan 6 was obtained in a moderate 59% yield. The conver-
sion of benzofuran 6 to coumestrol 1 was carried out by
using a one-pot protocol: First, removal of the methyl
groups (BBr3, 6 equiv, CH2Cl2, RT, overnight) afforded the
intermediate 6’ (not isolated). Thereafter, by switching the
solvent to boiling ethanol, the lactonization step was accom-
plished, and the resulting insoluble yellowish solid was fil-
tered off to afford pure coumestrol (1) in 97% yield. To
[a] All reactions were carried out with 2c (0.5 mmol) and 3c (0.65 mmol)
in DCE (0.25m) at 1008C for 24 h. [b] Yields of the product. [c] Yields
determined by NMR spectroscopy are given in square brackets. [d] 48 h
in DCE or 9 h in toluene. 1,3,5-trimethoxy benzene was used as the inter-
nal standard. NHPI=N-hydroxyphthalimide
ethyl 2-(2-methoxybenzoyl)acetate (2d) and phenol (3d) af-
forded benzofuran 9 (73% yield), which was converted to
coumestan in 90% yield. Compound 22 was synthesized
starting from b-ketoester 2c and 3,4-dimethoxyphenol (3 f)
in 52% yield for the two steps. This compound could be
converted to the medicagol natural product in a single syn-
thetic step.[31] Whereas ethyl 2-benzoylacetates having a
single ortho-methoxy group (such as 2c and 2d) reacted
well and the method could be applied in the synthesis of
Chem. Eur. J. 2013, 00, 0 – 0
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
&
3
&
ÞÞ
These are not the final page numbers!

D. Pappo et al.
many members of the coumestan family, other ethyl 2-ben-
zoylacetates having two ortho-substituents, such as ethyl 2-
(4-bromo-2,6-dimethoxybenzoyl)acetate and ethyl 2-(6-
bromo-2,4-dimethoxybenzoyl)acetate, which upon successful
coupling could provide an entry to wedelolactone natural
product,[17] were found to be inactive.
(Scheme 5) was detected in 75% yield by using NMR spec-
troscopy (FeCl3·ACTHUNTRGNE(UNG H2O)6/DTBP catalytic system), however it
was contaminated with Friedel–Crafts alkylation byproducts.
Although the coupling of phenols 2 and b-ketoesters 3
provides easy access to variety of coumestrol derivatives,
the reaction requires the use of the hazardous DTBP as the
oxidant.[11,12] Indeed, one of the weaknesses of many of the
CDC reactions is the need for organic oxidants that consti-
tute safety concerns, which are particularly troublesome for
future industrial applications. Since Li and co-workers re-
ported the first example of an iron-CDC reaction in 2007,[32]
most of the transformations developed subsequently have
required the use of organic oxidants such as DTBP
(tBuOOtBu),[33] TBHP (tBuOOH)[34] or 2,3-dichloro-5,6-di-
cyano-1,4-benzoqinone (DDQ).[1c,35] Exceptions are the al-
kylation reaction of 1,3-dicarbonyl compounds and benzylic
substrates in the presence of FeCl2, CuCl, and N-hydroxyph-
thalimide (NHPI) under an oxygen atmosphere[36] and Kat-
Scheme 5. FeCl3/O2 Oxidative coupling of b-ketoesters with phenols.
As a result, a pure compound 7 could only be obtained by
preparative-HPLC separation and in an unreported yield of
the isolated product.[11] Under our modified aerobic cou-
pling conditions benzofuran 7 was isolated in 55% yield.
Moreover, sensitive phenols, such as 2-methoxyphenol (3e,
Scheme 5), which had failed to react when DTBP was used
as the oxidant, now became a suitable partner; benzofuran 8
was obtained in 24% yield.
sukiꢁs FeACHTUNGTRENNUNG(salan) complex, which catalyzes enantioselective
aerobic oxidative cross-coupling reactions of naphthol deriv-
atives.[4,37]
The NHPI/O2 oxidation system was assumed to be a good
solution not only from the safety point of view, but also be-
cause it facilitates more environmentally friendly and eco-
nomical reactions and, in the case of phenol coupling reac-
tions, it should eliminate the Friedel–Crafts alkylation side
reaction that occurs with DTBP and TBHP. The oxidative
abilities of the NHPI/O2 system in hydrocarbon oxidations
has been studied extensively and reviewed,[38] and the ability
of that system to oxidize FeIII to FeIV species in CH oxida-
tion reactions has also been reported.[39] Therefore, it was
logical to explore that direction. Indeed, when ethyl 2-(2,4-
dimethoxybenzoyl)acetate (2c, 1 equiv) and 3-methoxyphe-
nol (3c, 1.3 equiv) were mixed in DCE at 1008C in the pres-
ence of FeCl3 (10 mol%) and NHPI (5 mol%) under an
oxygen atmosphere (O2 balloon), the reaction went to com-
pletion within 24 h, isolating the coupling product 6 in 61%
yield (Table 1, entry 1). Increasing the amount of NHPI to
20 mol% had a negative effect on the yield (53%, Table 1,
entry 2). Furthermore, when the reaction was performed in
the absence of NHPI, benzofuran 6 was isolated in a moder-
ate 63% yield (Table 1, entry 3), which indicates that NHPI
does not play a role in the reaction mechanism. The addi-
tion of 2,2’-bipyridine (5 mol%) to the reaction mixture
slowed down the process, and after 24 h only partial conver-
sion was observed (Table 1, entry 4). To simplify the method
even further, we performed the reaction under air atmos-
phere (open flask). Whereas the reaction in DCE was much
slower and required a longer reaction time (48 h), the reac-
tion in toluene went to completion in only 9 h. In both
cases, the desired coupling product 6 was isolated in 52%
yield. In addition, the modified conditions were examined
for the coupling of ethyl benzyloxyacetate (2a) with phenol
Encouraged by the success of our syntheses, we shifted
our attention to the synthesis of unnatural coumestrol ana-
logues suitable for a structure–activity relationship study.
Based on preliminary biology results (see below), 2-benzy-
loxyacetates 2c and 2d were chosen as the coupling partners
for building our library. These b-ketoesters were thus treat-
ed with a variety of phenol derivatives by using the FeCl3/bi-
pyridine/DTBP catalytic system (Table 2). The oxidative
coupling reaction of compounds 2c and 2d with phenols
bearing meta and para electron-neutral and electron-rich
substituents (3c–3i) afforded benzofurans 9–15 in moderate-
to-good yields (53–77%; Scheme 4 and Table 2, entries 1–7).
Electron-deficient phenols bearing p-Br (3j), p-F (3k) and
p-CF3 (3l) groups were also found to be good partners, and
benzofurans 16–18 were isolated in 65, 73, and 51% yields,
respectively. Less-activated phenols, such as 4-cyanophenol,
4-formylphenol and 4-(ethoxycarbonyl)phenol, failed to
react. For comparison reasons, our modified aerobic oxida-
tive coupling conditions were also examined affording the
desired products in moderate yields.
The conversion of benzofurans 9–18 and 19 to the corre-
sponding coumestrol analogues was performed in good-to-
excellent yields by using the deprotection–lactonization pro-
tocol developed for the synthesis of coumestrol (BBr3 in
CH2Cl2, then boiling ethanol). However, initial attempts to
convert benzofuran 18 bearing the trifluoromethyl group af-
forded the 9-ethoxycarbonyl-coumestrol derivative 29 in
84% yield, as a result of acid-catalyzed alcoholysis of the
acid-sensitive CF3 group.[40] Alternatively, when compound
18 was first deprotected with BBr3 (CH2Cl2, room tempera-
ture) and then heated at reflux in toluene in the presence of
a catalytic amount of triethylamine (50 mol%) for 30 min,
(3d). Previously, the corresponding benzofuran
7
&
4
&
www.chemeurj.org
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 0000, 00, 0 – 0
ÝÝ
These are not the final page numbers!

Aerobic Iron-Based Cross-Dehydrogenative Coupling
FULL PAPER
Table 2. Synthesis of coumestans (compounds 20–31) through the direct coupling of b-ketoesters (2) and phenols (3).[a]
Entry
1
b-Ketoester
Phenol
Benzofuran
“DTBP”
“Aerobic”
yield [%][b]
Coumestan
Yield
[%][b]
yield [%][b]
3d
73
55
53
77
58
63
68
65
73
–
90
89
89
83
91
92
93
85
97
2
3
4
5
6
7
8
9
2d
3c
3 f
3d
3g
3h
3i
34
–
2c
2c
2c
2c
2c
2c
–
51
–
56
23
–
3j
3k
10
11
12
2c
–
3l
–
51
–
–
–
–
83
–
92[c]
2c
3a
65
67
[a] i) “DTBP” conditions: 2 (1 mmol), 3 (1.1 mmol), FeCl3 (10 mol%), 2,2’-bipyridine (5 mol%), tBuOOtBu (2 mmol), DCE (0.5m), 708C, N2 atmos-
phere; “aerobic” conditions: 2 (1 mmol), 3 (1.1 mmol), FeCl3 (10 mol%), DCE (0.5m), 1008C, O2 atm; ii) 7, BBr3 (1m in CH2Cl2), CH2Cl2, RT, then
EtOH, reflux. [b] Yield of the isolated product. [c] Alternative conditions: 18, triethylamine (TEA, 50 mol%), toluene, 708C, 1 h.
the desired 3-trifluoromethylcoumestrol 30 was isolated in
92% yield after column chromatography; previous attempts
to prepare CF3-substituted coumestan derivatives by using
different synthetic approaches failed.[28]
Chem. Eur. J. 2013, 00, 0 – 0
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
&
5
&
ÞÞ
These are not the final page numbers!

D. Pappo et al.
Biological evaluation: In parallel to our synthetic effort to
establish the methodology for the synthesis of coumestrol
and coumestrol analogues based on CDC technology, we
sought to utilize the developed chemistry in a structure–ac-
tivity relationship study of 1. For that purpose, molecular-
modeling techniques together with estrogenic response eval-
uations were integrated with our synthetic capabilities.
With the aim of designing a library of SERMs based on
coumestrol, we examined the binding mode of the natural
product in the estrogen receptor ligand-binding site by using
computational modeling techniques. The dimensions of the
ER binding sites, as reflected in many solved crystal struc-
tures,[41] suggest that the recognition of coumestrol takes
place inside the hydrophobic pocket in one of two direction-
ally different binding modes, as presented in Figure 2: either
the 3-hydroxy group or the 9-hydroxy group interacts
through a hydrogen bond with a buried water molecule in
the structurally conserved polar pocket formed by the Glu305
and Arg346 residues (binding models A and B, respectively,
Figure 2). In both cases, several hydrophobic interactions
with surrounding hydrophobic amino acids (such as Leu298
and Phe356) restrict the conformational freedom of the
ligand. Finally, the remaining hydroxyl group can bind at the
end of the cavity with the flexible His475 residue.[41] The two
different binding models represent inverted conformational
arrangements of 1 in the hydrophobic pocket.[42] An X-ray
co-crystal structure of coumestrol complexed to ERa or
ERb would provide the needed evidence as to the preferred
binding form of coumestrol, but such a crystal structure is
not available.
The difference in pKa values of the two hydroxyl groups
(7.5 and 9.1, for the 3- and 9-hydroxyl groups, respective-
ly),[45] the structures of co-crystals of ERa and ERb with
other ER ligands,[43] and the structure of co-crystal of cou-
mestrol with 17b-HSD (17b-hydroxysteroid dehydrogen-
ase)[46] all indicate that the conformation in which the 3-hy-
droxy group interacts with the Glu305 and Arg346 residues
(binding model A) is the more likely of the two options. To
provide support for this premise, the proliferation of the
ER-positive breast cancer line, MCF-7, was evaluated in re-
sponse to exposure to 9-hydroxycoumestan 21 and 3-
Figure 2. Schematic representation showing the interactions between cou-
mestrol (1) and ERb-ligand binding domain (LBD) (1U9E).[44] Zoom-in
view of two possible coumestrol binding modes that are dependent on
the hydroxyl location. a) Coumestrol (yellow sticks) is directed by the 3-
hydroxy group (binding model A); b) Coumestrol (pink sticks) is directed
by the 9-hydroxy (binding model B). ERb-LBD is represented as green
sticks and ribbons. Overall, red represents oxygen atoms and blue repre-
sents nitrogen atoms.[44]
hydroxyACHTUNGTRENNUNG
coumestan 23.[47] Whereas compound 23 exhibited
moderate activity, with an IC50 value of 153 nm (Table 3,
entry 5), 9-hydroxycoumestan 21 was inactive at concentra-
tions lower than 10À6 m (entry 3). Moreover, coumestan 20,
which lack the two-hydroxyl groups, was found to be inac-
tive as well. These results support our hypothesis that the 3-
hydroxy group is important for binding to the ER, and in
terms of structure–activity considerations the 9-hydroxy
group can be removed and replaced with other substituents.
To provide proof that the inhibitory effect of our com-
pounds on MCF-7 breast cancer cells is indeed ER-depend-
ent, all the compounds were tested against the estrogen-in-
dependent MDA-MB-321 breast cancer cell line.[47] Not sur-
prisingly, all tested compounds were found to be inactive
against these cells at wide range of concentrations (from
10À6 to 10À9 m), showing that the activity of our modified
coumestrol derivatives does indeed involve binding to the
ER. Moreover, these results indicate that the tested com-
pounds are not toxic to other cellular processes beyond the
ones that are regulated by the ER. The results for selected
compounds are given in Figure 3.
In this study, we addressed only the estrogenicity of cou-
mestrol derivatives having different substituents at the C8
and C9 positions. The effects of all the compounds on the
proliferation response of the MCF-7 estrogen-dependent
cells was evaluated at different concentrations (10À6 to
10À9 m), and the IC50 values are given in Table 3. The superi-
or anti-proliferative activity of coumestrol over other mem-
bers of the coumestan family[14] is in consistent with our
findings that synthetic coumestans (20–24) having oxygena-
tion patterns that differ from the pattern of coumestrol 1
&
6
&
www.chemeurj.org
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 0000, 00, 0 – 0
ÝÝ
These are not the final page numbers!

Aerobic Iron-Based Cross-Dehydrogenative Coupling
FULL PAPER
Table 3. Inhibition of proliferation of MCF-7 breast cancer cells by cou-
mestrol and its derivatives and by synthetic coumestans.[a]
Entry
Compound
R1
R2
R3
IC50
AHCTUNGTRENNUNG
[10À9 m][b]
1
2
3
4
5
6
7
8
9
10
11
12
13
1
20
21
22
23
24
25
26
27
28
29
30
31
OH
H
H
OH
H
OH
OH
H
H
NHAc
H
H
H
H
H
H
H
H
OH
H
OH
H
NHAc
Br
73Æ38
NA[c]
NA[c]
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
NA[c]
153Æ12
NA[c]
30Æ19
9Æ5
NA[c]
F
220Æ51
58Æ2
170Æ17
180Æ42
CO2Et
CF3
Figure 4. Zoom-in view of 9-acetamidocoumestrol (25) (light-purple
sticks) docked into ERb-LBD (green sticks and ribbons). Red represents
oxygen atoms, and blue represents nitrogen atoms.
naphthyl
[a] For experimental details see the Supporting Information. [b] IC50
=
the concentration of the compound that leads to 50% inhibition of cell
survival ÆSEM values. [c] NA=not active at concentrations lower than
10À6 m.
ligand are located in the correct position and orientation to
form a hydrogen bond with the His475 residue. In addition,
hydrophobic interactions can take place between the acet-
amide group of 25 with close hydrophobic amino acid resi-
dues such as Leu476 (ꢀ2.5 ꢂ distance), Met479 (ꢀ2.8 ꢂ),
Met295 (ꢀ3.1 ꢂ), and Thr299 (ꢀ3.4 ꢂ). Studies of the dock-
ing of compound 26 having an acetamide group at C8 into
the ERb ligand-binding domain showed only poor compati-
bility at the end of the cavity, which suggests that upon bind-
ing a conformational change of the protein must occur.
Indeed, a previous structural study of ERs has shown that
the conformational flexibility of the ER allows it to exist in
a spectrum of conformations, from active to inactive, de-
pending on the nature of the binding ligand.[21b]
Importantly, our results on the inhibitory effect of cou-
mestrol in the proliferation of MCF-7 cells are not in agree-
ment with the observations of Matsumara et al. who report-
ed that coumestrol leads to a concentration-dependent en-
hancement in the proliferation of MCF-7 cells.[49] This dis-
crepancy in the results could be explained by the differences
in the culture conditions used by the two laboratories.
Despite the fact that the incorporation of an amide group
into SERMs seems logical, we could not find any precedents
for such an approach, and we intend to investigate this di-
rection further in the future. Hopefully, in the long-term,
this work will open the way to the development of a new
class of SERMs for the treatment of breast cancer and other
diseases associated with ERs.
Figure 3. The proliferative response of selected compounds on estrogen-
dependent (MCF-7) and estrogen-independent (MDA-MB-231) cells at
10À7 m after 6 days in culture. MCF-7 cells and MDA-MB-231 cells were
cultured in DCS/MEM for 1 week. Cells were plated in 96-well plates
(5,000 cells/well and 2500 cells/well, respectively, in 100 mL of medium),
allowed to attach overnight, and treated the next day (day 0). Cell surviv-
al was quantified by using the thiazolyl blue tetrazolium bromide (MTT)
assay.[48] Data represents the mean of two experiments (four wells for
every treatment in every experiment) ÆSEM values.
are at least one order of magnitude less active. However,
when the 9-hydroxyl group was replaced with hydrophobic
groups such 8-CF3 (30) or a fused ring, as in naphthocou-
mestrol 31, the estrogenic activity was increased, with IC50
values of 170 and 180 nm, respectively.
The substitution of the 9-hydroxy group of coumestrol
with 8-CO2Et (29), 9-NHAc (25), or 8-NHAc (26) groups
resulted with improved estrogenic activity, with IC50 values
of 58, 30, and 9 nm, respectively. A docking study of 9-acet-
amidocoumestrol (25) into the ligand-binding domain of
ERb (Figure 4) suggests that the NH atoms of the latter
Conclusion
This work describes the first application of the CDC strat-
egy in target- and diversity-oriented synthesis. We have de-
veloped an efficient, scalable, economical, and sustainable
synthesis of coumestrol based on aerobic iron oxidative
Chem. Eur. J. 2013, 00, 0 – 0
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
&
7
&
ÞÞ
These are not the final page numbers!

D. Pappo et al.
6.86–6.98 ppm (m, 3H); 13C NMR (100 MHz, [D6]DMSO): d=161.7,
160.1, 158.2, 157.5, 156.5, 155.2, 123.3, 121.2, 115.1, 114.6, 114.3, 104.7,
103.6, 102.6, 99.2 ppm.
cross-coupling of phenols with ethyl 2-benzoylacetate deriv-
atives. A preliminary SAR study was performed in which
the coumestrol derivatives prepared in this study were
found to inhibit the proliferation of estrogen-dependent
MCF-7 breast cancer cells but not of estrogen-independent
MDA-MB-321 breast cancer cells, suggesting that these
compounds act through the ERs. In addition, the impor-
tance of the 3-hydroxy group for the anti-proliferative activ-
ity was demonstrated, and an improved estrogenic activity
was found when the 9-hydroxy group found in the natural
product was replaced with an acetamide group. Whereas the
inhibitory activity of 9-acetamidocoumestrol (25) of MCF7
cell proliferation was found to be of the same order of mag-
nitude as that of the natural compound coumestrol 1, 8-acet-
amidocoumestrol (26) was about 8 times more active than 1.
As part of the interest of our group in developing new
methods for the functionalization of phenols based on
copper and iron oxidative coupling reactions, we intend to
further apply the developed chemistry in the diversity-ori-
ented synthesis of phenolic compounds of pharmacological
interest. In addition, structure–activity analysis of com-
Acknowledgements
We wish to thank Dr. Amira Rudi (BGU) for NMR spectroscopic assis-
tance and Prof. Ashraf Brik (BGU) for useful discussions. U.A.K is
grateful to the PBC fellowship program. This research was supported by
the Israel Science Foundation (Grant No. 1406/11).
[1] a) C. S. Yeung, V. M. Dong, Chem. Rev. 2011, 111, 1215–1292; b) C.
Liu, H. Zhang, W. Shi, A. Lei, Chem. Rev. 2011, 111, 1780–1824;
c) C.-L. Sun, B.-J. Li, Z.-J. Shi, Chem. Rev. 2011, 111, 1293–1314.
[2] C.-J. Li, Acc. Chem. Res. 2009, 42, 335–344.
[3] a) W. Liu, J. Liu, D. Ogawa, Y. Nishihara, X. Guo, Z. Li, Org. Lett.
2011, 13, 6272–6275; b) H.-F. Jiang, J.-H. Li, Z.-W. Chen, Tetrahe-
dron 2010, 66, 9721–9728; c) C. M. R. Volla, P. Vogel, Org. Lett.
2009, 11, 1701–1704; d) Y.-Z. Li, B.-J. Li, X.-Y. Lu, S. Lin, Z.-J. Shi,
Angew. Chem. 2009, 121, 3875–3878; Angew. Chem. Int. Ed. 2009,
48, 3817–3820; e) C.-X. Song, G.-X. Cai, T. R. Farrell, Z.-P. Jiang,
H. Li, L.-B. Gan, Z.-J. Shi, Chem. Commun. 2009, 6002–6004; f) X.
Guo, S. Pan, J. Liu, Z. Li, J. Org. Chem. 2009, 74, 8848–8851; g) L.
Zhao, C.-J. Li, Angew. Chem. 2008, 120, 7183–7186; Angew. Chem.
Int. Ed. 2008, 47, 7075–7078; h) Z. Li, R. Yu, H. Li, Angew. Chem.
2008, 120, 7607–7610; Angew. Chem. Int. Ed. 2008, 47, 7497–7500;
i) Y. Zhang, C.-J. Li, Eur. J. Org. Chem. 2007, 4654–4657; j) Y.
Zhang, C.-J. Li, Angew. Chem. 2006, 118, 1983–1986; Angew. Chem.
Int. Ed. 2006, 45, 1949–1952; k) Z. Li, D. S. Bohle, C.-J. Li, Proc.
Natl. Acad. Sci. USA 2006, 103, 8928–8933; l) Z. Li, C.-J. Li, J. Am.
Chem. Soc. 2005, 127, 3672–3673; m) Z. Li, C.-J. Li, J. Am. Chem.
Soc. 2004, 126, 11810–11811; n) Z. Li, C.-J. Li, J. Am. Chem. Soc.
2005, 127, 6968–6969.
pounds 25 and 26 and others in the ERACHTNUTRGNEUNG(a and b) ligand-
binding domains, assessment of the selectivity for ER subu-
nits of the new class of SERMs and further study of their
mode of action are also part of our ongoing medicinal-
chemistry program.
Experimental Section
[4] H. Egami, K. Matsumoto, T. Oguma, T. Kunisu, T. Katsuki, J. Am.
Chem. Soc. 2010, 132, 13633–13635.
Ethyl-2-(2,4-dimethoxyphenyl)-6-methoxybenzofuran-3-carboxylate (6):
A
stirred solution of ethyl 3-(2,4-dimethoxyphenyl)-3-oxopropanoate
[5] P. A. Wender, B. L. Miller, Nature 2009, 460, 197–201.
[6] a) K. C. Nicolaou, R. Reingruber, D. Sarlah, S. Brase, J. Am. Chem.
Soc. 2009, 131, 2086–2087; b) M. P. DeMartino, K. Chen, P. S.
Baran, J. Am. Chem. Soc. 2008, 130, 11546–11560; c) E. S. Krygow-
ski, K. Murphy-Benenato, M. D. Shair, Angew. Chem. Int. Ed. 2008,
47, 1680–1684; d) P. S. Baran, T. J. Maimone, J. M. Richter, Nature
2007, 446, 404–408; e) P. S. Baran, N. B. Ambhaikar, C. A. Guer-
rero, B. D. Hafensteiner, D. W. Lin, J. M. Richter, ARKIVOC 2006,
7, 310–325; f) R. H. Frazier, Jr., R. L. Harlow, J. Org. Chem. 1980,
45, 5408–5411.
[7] A. A. O. Sarhan, C. Bolm, Chem. Soc. Rev. 2009, 38, 2730–2744.
[8] D. Barton, A. Deflorin, O. Edwards, J. Chem. Soc. 1956, 530–534.
[9] H. Eickhoff, G. Jung, A. Rieker, Tetrahedron 2001, 57, 353–364.
[10] a) M. Chandrasekharam, B. Chiranjeevi, K. S. V. Gupta, B. Sridhar,
J. Org. Chem. 2011, 76, 10229–10235; b) H.-P. Bi, W.-W. Chen, Y.-
M. Liang, C.-J. Li, Org. Lett. 2009, 11, 3246–3249.
(2 g, 7.94 mmol, 1 equiv), 3-methoxy phenol (1.08 g, 8.73 mmol, 1 equiv),
and FeCl3 (0.13 g, 0.8 mmol, 0.1 equiv) in 1,2-dichloroethane (0.5m)
under an oxygen atmosphere was heated to 1008C for 24 h. The mixture
was cooled to room temperature, quenched with saturated NaHCO3
(10 mL), and extracted with EtOAc (3ꢃ10 mL). The combined organic
layer was washed with saturated NaHCO3 (10 mL) and water (10 mL)
and dried over Na2SO4. The solvent was filtered and removed under re-
duced pressure, and the residue purified by flash column chromatography
over silica gel (ethyl acetate/hexanes, 1:4) affording compound 6 (1.72 g,
63%) as a white solid. 1H NMR (400 MHz, CDCl3): d=7.88 (d, J=
8.6 Hz, 1H), 7.48 (d, J=8.5 Hz, 1H), 7.04 (d, J=2.2 Hz, 1H), 6.96 (dd,
J=8.6, 2.2 Hz, 1H), 6.59 (dd, J=8.5, 2.2 Hz, 1H), 6.54 (d, J=2.2 Hz,
1H), 4.3 (q,J=7.1 Hz, 2H), 3.86 (s, 3H), 3.85 (s, 3H), 3.79 (s, 3H),
1.29 ppm (t, J=7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3): d=164.0,
162.4, 158.9, 158.1, 157.6, 154.9, 132.3, 122.0, 120.0, 112.5, 112.2, 110.3,
104.3, 98.6, 95.6, 60.1, 55.6, 55.5, 55.4, 14.2 ppm; IR (KBr): n˜ =1700.9,
1623.8, 1500.4 cmÀ1; HRMS (ESI): m/z calcd for C20H21O6: 357.1332
[M+H]+; found: 357.1323.
[11] X. Guo, R. Yu, H. Li, Z. Li, J. Am. Chem. Soc. 2009, 131, 17387–
17393.
[12] R. Parnes, U. A. Kshirsagar, A. Werbeloff, C. Regev, D. Pappo, Org.
Lett. 2012, 14, 3324–3327.
Coumestrol (1): A solution of BBr3 (1m in DCM, 29 mL, 0.029 mol) was
added dropwise to a stirred solution of benzofuran 6 (1.72 g, 4.83 mmol)
in dry CH2Cl2 (50 mL) at 08C under a nitrogen atmosphere. The mixture
was allowed to warm to room temperature and further stirred overnight.
After quenching the reaction with EtOH (1 mL), the volatiles were re-
moved under reduced pressure, and the residue was dissolved in EtOH
(5 mL). The mixture was heated at reflux for 3 h until TLC showed com-
plete conversion. The mixture was cooled to room temperature and the
desired product was filtered off, washed with EtOH (1 mL) and dried
under vacuum, affording coumestrol (1.26 g, 97%) as a yellow solid.
1H NMR (400 MHz, [D6]DMSO): d=10.71 (s, 1H), 10.04 (s, 1H), 7.85
(d, J=8.1 Hz, 1H), 7.68 (d, J=8.5 Hz, 1H), 7.16 (d, J=2.0 Hz, 1H),
[13] A. L. Ososki, E. J. Kennelly, Phytother. Res. 2003, 17, 845–869.
[14] M. S. Kurzer, X. Xu, Annu. Rev. Nutr. 1997, 17, 353–381.
[15] K. R. Price, G. R. Fenwick, Food Addit. Contam. 1985, 2, 73–106.
[16] P. A. Melo, D. A. Pinheiro, H. D. Ricardo, F. F. A. Fernandes, M. A.
Tomaz, C. Z. El-Kik, M. A. Strauch, F. T. F. da, D. N. Sifuentes, S.
Calil-Elias, C. D. Buarque, F. V. Brito, P. R. R. Costa, S. A. J. M. Da
Silva, Toxicon 2010, 55, 488–496.
[17] a) K. W. Gaido, L. S. Leonard, S. Lovell, J. C. Gould, D. Babai, C. J.
Portier, D. P. McDonnell, Toxicol. Appl. Pharmacol. 1997, 143, 205–
212; b) C. C. Li, Z. X. Xie, Y. D. Zhang, J. H. Chen, Z. Yang, J. Org.
Chem. 2003, 68, 8500–8504.
&
8
&
www.chemeurj.org
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 0000, 00, 0 – 0
ÝÝ
These are not the final page numbers!

Aerobic Iron-Based Cross-Dehydrogenative Coupling
FULL PAPER
[18] a) E. M. Bickoff, R. L. Lyman, A. L. Livingston, A. N. Booth, J. Am.
Chem. Soc. 1958, 80, 3969–3971; b) E. M. Bickoff, A. N. Booth,
R. L. Lyman, A. L. Livingston, C. R. Thompson, F. Deeds, Science
1957, 126, 969–970.
[28] L. Tang, Y. Pang, Q. Yan, L. Shi, J. Huang, Y. Du, K. Zhao, J. Org.
Chem. 2011, 76, 2744–2752
[29] Ethyl 2-(2,4-dimethoxbenzoyl)acetate is commercially available. In
this study we have prepared it from 2’,4’-dimethoxyacetophenone
(NaH, diethylcarbonate, toluene).
[19] a) M. S. Kurzer, J. Nutr. 2003, 133, 1983S–1986S;
[30] Both 2,2’-bipyridine and 1,10-phenanthroline can be used as addi-
tives in this reaction.
[31] A. L. Livingston, S. C. Witt, R. E. Lundin, E. M. Bickoff, J. Org.
Chem. 1965, 30, 2353–2355.
[32] Z. Li, L. Cao, C. J. Li, Angew. Chem. 2007, 119, 6625–6627; Angew.
Chem. Int. Ed. 2007, 46, 6505–6507.
[33] P. Liu, Z. Wang, J. Lin, X. Hu, Eur. J. Org. Chem. 2012, 1583–1589.
[34] W. Liu, Y. Li, K. Liu, Z. Li, J. Am. Chem. Soc. 2011, 133, 10756–
10759.
[35] G. Zhang, Y. Zhang, R. Wang, Angew. Chem. 2011, 123, 10613–
10616; Angew. Chem. Int. Ed. 2011, 50, 10429–10432.
[36] C. A. Correia, C.-J. Li, Tetrahedron Lett. 2010, 51, 1172–1175.
[37] a) H. Egami, T. Katsuki, J. Am. Chem. Soc. 2009, 131, 6082–6083;
b) T. Oguma, T. Katsuki, J. Am. Chem. Soc. 2012, 134, 20017–
20020.
[38] F. Recupero, C. Punta, Chem. Rev. 2007, 107, 3800–3842.
[39] S. H. Cho, M. S. Cheong, K. D. Jung, C. S. Kim, S. H. Han, Appl.
Catal., A 2004, 267, 241–244.
[40] K. Ramig, M. Englander, F. Kallashi, L. Livchits, J. Zhou, Tetrahe-
dron Lett. 2002, 43, 7731–7734.
[41] P. Ascenzi, A. Bocedi, M. Marino, Mol. Aspects Med. 2006, 27, 299–
402.
[42] The size of the hydrophobic pocket permits the rotation of ligands
around their horizontal axis (not shown); however, the shape of the
polar pocket restricts the phenol group to a specific position and ori-
entation.
[43] E. S. Manas, R. J. Unwalla, Z. B. Xu, M. S. Malamas, C. P. Miller,
H. A. Harris, C. Hsiao, T. Akopian, W.-T. Hum, K. Malakian, S.
Wolfrom, A. Bapat, R. A. Bhat, M. L. Stahl, W. S. Somers, J. C. Al-
varez, J. Am. Chem. Soc. 2004, 126, 15106–15119.
[44] Details regarding the docking methods are given in the Supporting
Information.
[20] S. Makela, V. L. Davis, W. C. Tally, J. Korkman, L. Salo, R. Vihko,
R. Santti, K. S. Korach, Environ. Health Perspect. 1994, 102, 572–
578.
[21] a) N. Heldring, A. Pike, S. Andersson, J. Matthews, G. Cheng, J.
Hartman, M. Tujague, A. Strom, E. Treuter, M. Warner, J. A. Gus-
tafsson, Physiol. Rev. 2007, 87, 905–931; b) B. J. Deroo, K. S.
Korach, J Clin Invest 2006, 116, 561–570.
[22] a) J. K. Hess-Wilson, J. Boldison, K. E. Weaver, K. E. Knudsen,
Breast Cancer Res. Treat. 2006, 96, 279–292; b) S. Gꢄlinas, M.-G.
Martinoli, J. Neurosci. Res. 2002, 70, 90–96; c) G. G. J. M. Kuiper, B.
Carlsson, K. Grandien, E. Enmark, J. Hꢅggblad, S. Nilsson, J.-ꢂ.
Gustafsson, Endocrinology 1997, 138, 863–870; d) G. G. J. M.
Kuiper, J. G. Lemmen, B. Carlsson, J. C. Corton, S. H. Safe, P. T. van
der Saag, B. van der Burg, J.-ꢂ. Gustafsson, Endocrinology 1998,
139, 4252–4263.
[23] C. Phillips, L. R. Roberts, M. Schade, R. Bazin, A. Bent, N. L.
Davies, R. Moore, A. D. Pannifer, A. R. Pickford, S. H. Prior, C. M.
Read, A. Scott, D. G. Brown, B. Xu, S. L. Irving, J. Am. Chem. Soc.
2011, 133, 9696–9699.
[24] L. R. Roberts, D. Armor, C. Barker, A. Bent, K. Bess, A. Brown,
D. A. Favor, D. Ellis, S. L. Irving, M. MacKenny, C. Phillips, N.
Pullen, A. Stennett, L. Strand, M. Styles, Bioorg. Med. Chem. Lett.
2011, 21, 5680–5683.
[25] A. K. Shiau, D. Barstad, J. T. Radek, M. J. Meyers, K. W. Nettles,
B. S. Katzenellenbogen, J. A. Katzenellenbogen, D. A. Agard, G. L.
Greene, Nat. Struct. Biol. 2002, 9, 359–364.
[26] a) T. Yao, D. Yue, R. C. Larock, J. Org. Chem. 2005, 70, 9985–9989;
b) N. Al-Maharik, N. P. Botting, Tetrahedron 2004, 60, 1637–1642;
c) G. A. Kraus, N. Zhang, J. Org. Chem. 2000, 65, 5644–5646; d) K.
Hiroya, N. Suzuki, A. Yasuhara, Y. Egawa, A. Kasano, T. Sakamoto,
J. Chem. Soc. Perkin Trans. 1 2000, 4339–4346; e) R. Laschober, T.
Kappe, Synthesis 1990, 387–388; f) S. B. Pandit, S. Y. Gadre, Synth.
Commun. 1988, 18, 157–166; g) O. H. Emerson, E. M. Bickoff, J.
Am. Chem. Soc. 1958, 80, 4381–4383.
[45] O. S. Wolfbeis, K. Schaffner, Photochem. Photobiol. 1980, 32, 143–
148.
ˇ
[46] A. Cassetta, I. Krastanova, K. Kristan, M. Brunskole Svegelj, D.
[27] < a) C.-F. Chang, L.-Y. Yang, S.-W. Chang, Y.-T. Fang, Y.-J. Lee,
Tetrahedron 2008, 64, 3661–3666; b) D.-H. Gong, C.-Z. Li, C.-Y.
Yuan, Chin. J. Chem. 2010, 19, 522–527; c) A. J. M. da Silva, P. A.
Melo, N. M. Silva, F. V. Brito, C. D. Buarque, D. V. de Souza, V. P.
Rodrigues, E. S. Pocas, F. Noꢆl, E. X. Albuquerque, P. R. Costa,
Bioorg. Med. Chem. Lett. 2001, 11, 283–286; d) B. S. U. Rani, M.
Darbarwar, J. Indian Chem. Soc. 1986, 63, 1060–1062; e) M. Darbar-
war, V. Sundaramurthy, N. V. S. Rao, Proc.-Indian Acad. Sci., Sect.
A 1974, 80, 93–96; f) H. W. Wanzlick, R. Gritzky, H. Heidepriem,
Chem. Ber. 1963, 96, 305–307; g) C. Deschamps-Vallet, C. Mentzer,
Compt. Rend. 1960, 251, 736–738.
ˇ
ˇ
Lamba, T. Lanisnik Rizner, J. Stojan, Biochemical J. 2012, 441, 151–
160.
[47] E. W. Thompson, D. Katz, T. B. Shima, A. E. Wakeling, M. E. Lipp-
man, R. B. Dickson, Cancer Res. 1989, 49, 6929–6934.
[48] N. Dudai, Y. Weinstein, M. Krup, T. Rabinski, R. Ofir, Planta Med.
2005, 71, 484–488.
[49] A. Matsumura, A. Ghosh, G. S. Pope, P. D. Darbre, J. Steroid Bio-
chem. Mol. Biol. 2005, 94, 431–443.
Received: January 31, 2013
Revised: June 12, 2013
Published online: && &&, 2013
Chem. Eur. J. 2013, 00, 0 – 0
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
&
9
&
ÞÞ
These are not the final page numbers!

D. Pappo et al.
Cross-Coupling
U. A. Kshirsagar, R. Parnes,
H. Goldshtein, R. Ofir, R. Zarivach,
D. Pappo* ..................... &&&& — &&&&
Green medicinal chemistry: An iron-
based cross-dehydrogenative coupling
(CDC) approach was applied for the
diversity-oriented synthesis of coumes-
trol-based selective estrogen receptor
modulators (SERMs), representing the
first application of CDC chemistry in
natural product synthesis (see scheme;
DCE=dichloroethane).
Aerobic Iron-Based Cross-Dehydro-
genative Coupling Enables Efficient
Diversity-Oriented Synthesis of
Coumestrol-Based Selective Estrogen
Receptor Modulators
&
10
&
www.chemeurj.org
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 0000, 00, 0 – 0
ÝÝ
These are not the final page numbers!