Biphenyls as surrogates of the steroidal backbone. Part 1: Synthesis and estrogen receptor affinity of an original series of polysubstituted biphenyls

Article abstract of DOI:10.1016/S0960-894X(01)00267-0

In the course of a programme aimed at discovering new ligands of the estrogen receptor, we explored a series of substituted biphenyls. Their synthesis and binding affinity are described.

Full text of DOI:10.1016/S0960-894X(01)00267-0

Bioorganic & Medicinal Chemistry Letters 11 (2001) 1709–1712
Biphenyls as Surrogates of the Steroidal Backbone.
Part 1: Synthesis and Estrogen Receptor Affinity of an Original
Series of Polysubstituted Biphenyls
Dominique Lesuisse,a,* Eva Albert,a Francoise Bouchoux,b E. Cerede,a
Jean-Michel Lefrancois,a Marc-Olivier Levif,a Sophie Tessier,a Bernadette Trica
and Georges Teutscha
aMedicinal Chemistry, Aventis, 102 route de Noisy, 93235 Romainville Cedex, France
bBone Diseases Group, Aventis, 102 route de Noisy, 93235 Romainville Cedex, France
Received 31 January 2001; revised 28 March 2001; accepted 18 April 2001
Abstract—In the course of a programme aimed at discovering new ligands of the estrogen receptor, we explored a series of sub-
stituted biphenyls. Their synthesis and binding affinity are described. # 2001 Elsevier Science Ltd. All rights reserved.
Introduction
use of the Suzuki coupling (Table 1, conditions 1–5) of
substituted phenylboronic acids12 with arylhalides or
triflates (entries 1–16). Even for 2,6-disubstituted aryl
triflates or bromides acceptable yields were obtained
(entries 3–8, 10, 11, 13–15). In the case of the coupling
of the 2,6-dimethyl 4-methoxy boronic acid only the
conditions described by Suzuki13 for the coupling of
hindered boronates with aryl iodides gave the product
in modest yield (entry 12). The absence of reactivity of
arylchlorides with boronic acids in the presence of tet-
rakis triphenylphopshine palladium has been reported
by Mitchell.14 All 2,6-disubstituted monochlorinated
aryl triflates or bromides gave reasonable yields of cou-
pling with boronic acids (entries 2, 6–8, 16). In the case
of 2,6-dichlorosubstituted aryl triflates (entry 3), about
30% chlorine monoreduction also occurred. This pro-
blem was eliminated when the iodides were used in place
of the triflates (entries 4, 14, 15), but the yields remained
modest especially when the arylboronic acids bore elec-
tron-withdrawing substituents. On the other hand, in
We have been actively involved during the past few
years in the search for new compounds with estrogenic
or antiestrogenic activities.1 Today, the main classes of
synthetic estrogens and antiestrogens are related to di2-
and tri3-aryl-methanes, -ethanes and ethylenes4 (e.g.,
DES5 and Tamoxifen6). The other well represented class
of nonsteroidal estrogen receptor ligands are the phe-
nolic indoles,7 indenes,8 thiophenes (e.g., Raloxifen9)
and pyrazoles.10 Because of the parallelism between 4-
hydroxy-40-hydroxymethyl-biphenyl and estradiol (Fig.
1) and stimulated by Korach’s report on estrogenic
activities in several hydroxybiphenyls,11 we became
interested in exploring a little more thoroughly this
potential new class of nonsteroidal estrogens.
The object of the present paper is to disclose the results
we have obtained with a series of these compounds and
their estrogen receptor binding affinities.
Chemistry
Most of the biphenyls described in this paper were
obtained by aryl–aryl coupling reactions (Scheme 1,
Table 1). Whenever substitution allowed for it, we made
*Corresponding author. Fax: +33-1-4991-5087; e-mail: dominique.
lesuisse@aventis.com
Figure 1.
0960-894X/01/$ - see front matter # 2001 Elsevier Science Ltd. All rights reserved.
PII: S0960-894X(01)00267-0

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D. Lesuisse et al. / Bioorg. Med. Chem. Lett. 11 (2001) 1709–1712
spite of the reported triflate versus bromide selective
coupling of a vinylstannane with an aryltriflate,15 in the
case of 2,6-dibromotriflate only low yields of expected
coupled product could be obtained (entry 5). We there-
fore had to devise a better way to obtain these 2,6-
dibromobiphenyls. For this, we made use of the repor-
ted selective Ullmann coupling reaction (Table 1, condi-
tions 6) for aryl halides having very different electronic
properties.16 The 2,6-dinitrochloro aromatic com-
pounds could be coupled smoothly with iodoaryl deri-
vatives (entries 17, 18). We also explored the synthesis
of these 2,6-dihalosubstituted biphenyls by a coupling
reaction using arylzinc reagents in the presence of palla-
dium17 (Table 1, condition 7). Kumada18 and Tilley19
have reported monocoupling reactions of arylzinc
reagents with dibromoaromatics. Encouraged by a
recent report by Grega20 describing biphenyl coupling
of a 2,6-difluoroaryl zinc with halopyridines, we first
turned to the synthesis of the fluorinated analogues of
our compounds using this method. 1,3-Difluoro-5-
tetrahydropyranyloxymethylbenzene was orthometal-
lated using BuLi and the lithium was exchanged with
zinc from a freshly prepared zinc chloride tetra-
hydrofuran solution. The resulting arylzinc reagent was
reacted with 4-benzyloxyphenylbromide at 50 ꢀC in the
presence of Pd(0) to give the desired compound (entry
19). Encouraged by the success of this reaction, we
applied it to the synthesis of the 2,6-dichlorobiphenyls.
Orthometallation of 1,3-dichlorobenzene has been
reported by Kress;21 the author reports that above 50 ꢀC
the lithium anion is unstable and gives rise to self-cou-
pling by substitution of the chlorine atoms. We proceeded
in the same way as for the difluorinated aromatics and
were able to obtain the expected 2,6-dichlorobiphenyls
(entries 20, 21). In the case of entry 21, the coupling
reaction was achieved selectively by displacement of the
bromo substituent of a bromochloroaromatic.22
The 2,6-dinitro biphenyls were further elaborated by
sequential reduction of the nitro groups using cyclohexene
Scheme 1.
Table 1. Synthesis of the functionalized biphenyl compoundsfjk
Entry
Compd
R1
R2
X
Y
R3
R4
R5
R6
Yield
Conditionsa
1
2
3
4
5
6
7
8
1
2
4
5
6
7
8
9
10
11
12
14
15
16
17
18
22
23
19
20
21
OMe
OBn
OSitBuPh2
OBn
OMe
—
—
—
—
—
—
—
—
—
—
—
Me
—
—
—
B(OH)2
B(OH)2
B(OH)2
B(OH)2
B(OH)2
B(OH)2
B(OH)2
B(OH)2
B(OH)2
B(OH)2
B(OH)2
B(OH)2
B(OH)2
B(OH)2
B(OH)2
B(OH)2
I
OTf
OTf
OTf
I
OTf
OTf
OTf
OTf
Br
—
Cl
Cl
Cl
Br
Cl
Cl
Cl
CF3
OMe
Me
—
Me
Cl
Cl
Cl
NO2
NO2
F
—
—
Cl
Cl
—
—
—
—
—
—
—
—
—
—
—
—
—
Cl
Cl
—
—
—
—
—
CHO
COOMe
CHO
100
55
43d
25g
6–10e
23
1
3
3
1
1
3
5
3
2
2
4
5
5
2
2
2
6
6
7
7
7
CH2(OCH2CH2O)
CHO
CHO
Br
OBn
OBn
OBn
OBn
OMe
iPr
CF3
—
OMe
Me
—
Me
Cl
Cl
—
NO2
NO2
F
Cl
Cl
CHO
CHO
CHO
CHO
CHO
CHO
OBn
26
85/23
85
39
29–40c
25
23
9
10
11
12
13
14
15
16
17
18
19
20
21
OBn
Br
OSitBuPh2
OMe
CHO
OBn
CHO
CHO
OSitBuMe2
OSitBuMe2
OBn
COOMe
OSitBuMe2
OTf
OTf
Br
I
I
Br
Cl
Cl
ZnCl
ZnCl
ZnCl
65
OBn
OSitBuMe2
COOMe
CH2O SitBuMe2
CH2OTHP
13h
59b
72
—
—
—
—
—
Cl, H
I
Br
Br
Br
39
58i
Cl
Cl
OSitBuMe2
CH(OCH2CH2O)
27c
17g
aConditions: (1): Na2CO3 2 M/LiCl/Pd(PPh3)4/EtOH/Tol/Á23; (2) Pd(PPh3)4/K3PO4/Dioxane/85 ꢀC;24 (3) Pd(PPh3)4/K3PO4 /KBr/Dioxane/85 ꢀC;
(4) Pd(PPh3)4/LiCl/Dioxane;14 (5) PdCl2(PPh3)2/Ba(OH)2/DME aq;13 (6) nBuLi/ꢁ78 ꢀC; ZnCl2/ꢁ78 ꢀC–rt; Pd(PPh3)4/THD/Á25 (7) Cu/120 ꢀC/
DMF.15
bDesilylated compound along with 16% of protected analogue.
cAfter silyl deprotection (TBAF/THF).
dContaining ca. 30% of monochlorinated analogue.
eAlong with 21% of compound resulting from coupling on the bromine atom and 10% of compound from double coupling on the bromine and the
triflate.
fMixture resulting mainly from double coupling on the bromine atoms.
gYield of three consecutive steps: iodination of 3,5-dichloro-1-dioxolano-benzene (BuLi/THF, NIS), coupling and acetal deprotection (HCl 1 N/
THF).
hYield of three consecutive steps: iodination of tetrachlorobenzyloxybenzene (BuLi/THF, NIS), coupling and aldehyde reduction (NaBH4/MeOH).
iAfter THP deprotection (HCl 2 N/MeOH).
jAs a mixture of methyl and butyl esters.
kAfter LAH reduction of the ester.

D. Lesuisse et al. / Bioorg. Med. Chem. Lett. 11 (2001) 1709–1712
1711
in the presence of palladium followed by transformation
of the resulting amine 25 into bromide,26 iodide,27
thioalkyl28 or pyrrole compounds 24–30 (Scheme 2).
The bromine and iodine atoms of these biphenyls could
be replaced by further coupling with propargylamines
as exemplified by the synthesis of 27.
affinity was then gained with the addition of a second
halogen atom with the 20,60-dibromo- and dichloro-
biphenyl 33 and 34 displaying, respectively, 425 and
104% of the receptor binding affinity of estradiol
(100%). This effect was partially lost when one of the
bromines was replaced by an iodine atom (35) and
totally abolished when both halogens were fluorines
(32). This first observation could be the result of steric
hindrance or of the reported slightly wider torsion angle
between the two aromatic rings when going from bro-
mine and chlorine to iodine.27 On the other hand, the
20,60-difluorobiphenyl has probably no more rotational
constraints than the unsubstituted biphenyl. The 20,60-
dinitro compound 49 still displayed about 25% of the
estradiol affinity, which was totally lost upon reduction
of one of the nitro groups to give the amine (50). This
observation is in line with previous reports in the lit-
erature that polar substituents are generally poorly
tolerated in the centre of the ligand binding pocket of
estrogen receptor alpha, at least in some nonsteroidal
ligands systems.30 Similarly, when one of the bromines
was replaced by a N-pyrrol-1-yl (44), the affinity was
also lost.
All these biphenyls were then further elaborated into
final compounds 30–59 (Table 2) possessing a free phe-
nol in the 4-position and a hydroxymethyl group in the
40-position using standard chemistry.
Biology
Receptor binding affinities (RBAs) for human recombi-
nant estrogen receptor alpha29 were determined accord-
ing to decribed procedures. Results were expressed as
percent of the affinity of estradiol.
In view of the aforementioned report that estrogenic
activities of several biphenyls were improved by con-
formational restriction brought about by one or two
ortho chlorines, we wanted to study polysubstituted
analogues of 30 with a special emphasis on halogen
dervivatives. Of all sites for substitution on the biphenyl
ring, the 20,60-position was best able to bring about
positive changes (Table 2). A detectable change of affi-
nity could be seen with the addition of a first chlorine in
the 20-position (31). Dramatic improvement of the
Obviously, conformational constraint was not the only
important factor for the estrogen receptor affinity since
replacement of the halogens by methoxy or methyl
groups resulted in total loss of affinity (47 and 48). Only
the trifluoromethyl group was capable of retaining some
affinity for the receptor (38 and 39). This effect of
Scheme 2.
Table 2. Estrogen receptor binding affinity of substituted biphenyls
R
Compd
REHa RBA
(%)
R
Compd
REHa RBA
(%)
—
30
31
32
33
34
<
2
20,60-Br,CCNMe2
20,60-Br,SMe
20,60-OMe2
45
46
47
48
49
0.2
4.5
0.24
0.8
24b
5
0.03
0
0
0.06
5,4
0
0.4
21
20-Cl
20,60-F2
20,60-Cl2
20,60-Br2
0.93
34 (104b)
106 (425 b
20,60-Me2
)
20,60-(NO2)
2
20,60-Br,I
35
36
37
38
39
40
41
42
43
44
41
2.5
22
50
9.5 (33b)
1
1
34
0.03
2
20,60-NO2, NH2
3,5-Br2
3,5-Me2
50
51
52
53
54
55
56
57
58
59
20,60-Cl, Ome
20,60-Cl, iPr
20,60-Cl,CF3
20-CF3
2,6-Me2
20,30,50,60-Cl4
2,3,5,6-Cl4
2,6-Cl2
20,60-[Cl,(4-HOPh)]
20-(4-HOPh)
20,60-Br,NO2
20,60-Br,NH2
20,60-Br,N-pyrrole
2-Cl-20,60-Cl2
2-Cl
3- CH2Ph-20,60-Cl2
0.03
0.07
32
aREH=Recombinant human estrogen receptor, 24 h/0 ꢀC.
bREH, 3 h/0 ꢀC.

1712
D. Lesuisse et al. / Bioorg. Med. Chem. Lett. 11 (2001) 1709–1712
trifluoromethyl groups has been described in the di-
ethylstilbestrol family.31
5. Korach, K. S.; Metzler, M.; McLachlan, J. A. Proc. Natl.
Acad. Sci. U.S.A. 1978, 75, 468. Korach, K. S.; Metzler, M.;
McLachlan, J. A. J. Biol. Chem. 1979, 254, 8963.
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8. Anstead, G. M.; Wilson, S. R.; Katzenellenbogen, J. A. J.
Med. Chem. 1989, 32, 2163. Anstead, G. M.; Peterson, C. S.;
Pinney, K. G.; Wilson, S. R.; Katzenellenbogen, J. A. J. Med.
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Mol. Pharmacol. 1991, 40, 806. Korach, K. S.; Chae, K.;
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see: Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457.
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instance: Fanta, P. E. Synthesis 1974, 1, 9.
Other positions were explored on the biphenyl scaffold
but no further improvement of the estrogen receptor
affinity could be obtained. Addition of more chlorine
atoms to 33 always resulted in diminished affinities (54
and 57). In this latter case, this had been observed also
by Korach in his series and was interpreted as a result of
the pKa difference between the tetra- and disusbtituted
aromatic compounds.
In addition, lipophilicity was not a very important
parameter since positioning of the two chlorine atoms in
the 2,6-positions of the first aromatic ring also resulted
in a total loss of affinity (56). Halogen substitution on
the first phenyl ring always gave very low affinities (51,
55, 58) as was the case for any substitution on this ring
(52 and 53). A bulky benzyl group in the 3-position
resulted in a total loss of affinity (cf. 59 with 33).
17. For a general review on transition metal catalyzed reac-
tions of organozinc reagents see: Erdik, E. Tetrahedron 1992,
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of coupling aryl Grignard reagents with 2,6-dichlorohalo aro-
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The Ullmann coupling of 1,3-dichloro-2-iodobenzene with
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Conclusion
Some simple scaffolds demonstrating excellent binding
affinities for the estrogen receptor were discovered. The
implications of these findings for future prospects in
estrogen or antiestrogen treatment are under investigation.
Acknowledgements
The authors are grateful to F. Nique and P. Vandevelde
for helpful discussions, and to the analytical department
for compound analyses.
References and Notes
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