Benzopyrans as selective estrogen receptor β agonists (SERBAs). Part 3: Synthesis of cyclopentanone and cyclohexanone intermediates for C-ring modification

Article abstract of DOI:10.1016/j.bmcl.2007.06.052

Benzopyrans are selective estrogen receptor (ER) β agonists (SERBAs), which bind the ER subtypes α and β in opposite orientations. Here we describe the syntheses of cyclopentanone and cyclohexanone intermediates for SAR studies of the C-ring on the benzop

Full text of DOI:10.1016/j.bmcl.2007.06.052

Bioorganic & Medicinal Chemistry Letters 17 (2007) 4824–4828
Benzopyrans as selective estrogen receptor b agonists
(SERBAs). Part 3: Synthesis of cyclopentanone and
cyclohexanone intermediates for C-ring modification
Timothy I. Richardson,* Jeffrey A. Dodge, Gregory L. Durst, Lance A. Pfeifer,
Jikesh Shah, Yong Wang, Jim D. Durbin, Venkatesh Krishnan and Bryan H. Norman
Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA
Received 17 April 2007; revised 13 June 2007; accepted 15 June 2007
Available online 20 June 2007
Abstract—Benzopyrans are selective estrogen receptor (ER) b agonists (SERBAs), which bind the ER subtypes a and b in opposite
orientations. Here we describe the syntheses of cyclopentanone and cyclohexanone intermediates for SAR studies of the C-ring on
the benzopyran scaffold. Modification of the C-ring disrupts binding to ERa, thus improving ERb selectivity up to 100-fold. X-ray
cocrystal structures confirm previously observed binding modes.
ꢀ 2007 Elsevier Ltd. All rights reserved.
The estrogen receptors are members of the steroid nucle-
ar hormone receptor family. ERa is important for devel-
opment and regulation of the female reproductive
system as well as maintenance of the skeletal and cardio-
vascular systems. ERb was discovered in 1996 in the rat
prostate gland and adds another layer of complexity to
our understanding of estrogen physiology.1 While ERa
is expressed in nearly all tissues of both sexes, ERb is ex-
pressed in the ovaries, uterus, and oviduct of the female
reproductive tract but not in breast tissue; while in
males, ERb is expressed in the prostate and epididymis
but not in the testes.2 Selective ER modulators (SERMs)
demonstrate tissue type functional selectivity with ago-
nist activity in bone, liver, and cardiovascular tissues,
and antagonist activity in the uterus and breast.3 This
tissue type functional selectivity is most likely due to
the interaction of ligand bound receptor with coactiva-
tors that combine to form gene transcription complexes
or interaction with corepressors that inhibit gene
transcription.
pyran 1a as a selective estrogen receptor b agonist
(SERBA-1).5 Recently we reported structure activity
relationship (SAR) studies focused on the size of the
3,4-fused ring labeled C in Figure 1.6 The addition of
a fused cyclopentane ring at the 3,4-carbon positions
of the benzopyran scaffold resulted in a dramatic in-
crease in binding affinity, 9-fold selectivity for ERb over
ERa, and provided us with a ligand architecture con-
taining structural elements that take advantage of the
space available above and below the plane marked by
the two phenol rings. As can be seen in Figure 1, the
cyclopropane is projected down from the plane marked
O
C-ring
SAR
HO
4
C
HO
3
A
B
O
O
2a
3a
O
O
D
OH
OH
SERBA-1, 1a
OH
HO
HO
ERα
Leu421
ERβ
Met373
Over the last decade several groups have reported ERb
selective ligands.4 Our own efforts focused on the benzo-
pyran scaffold resulting in the development of benzo-
O
ERα
ERβ
Leu384
Met336
Keywords: Estrogen; Estrogen receptor b; ERb; ERb; Selective estro-
gen receptor b agonist; SERBA.
Corresponding author. Tel.: +1 317 433 2372; fax: +1 317 433
0552; e-mail: t_richardson@lilly.com
O
3b
OH
*
Figure 1. Unique structural features of the benzopyran platform.
0960-894X/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2007.06.052

T. I. Richardson et al. / Bioorg. Med. Chem. Lett. 17 (2007) 4824–4828
4825
by the phenol rings. This unique structural feature al-
lowed us to take advantage of the Met-421 ! Ile-373
and the Leu-384 ! Met-336 differences between the
binding pockets of ERa ! ERb. Here we describe the
syntheses of cyclopentanone 2a and cyclohexanones 3a
and 3b. The ketone functional groups of these late stage
intermediates served as handles to perform SAR studies
of the C-ring on the benzopyran scaffold.
tecting groups of 13 could be removed under mildly
acidic aqueous conditions to give cyclopentanone 2a.
The use of cyclopentanone 13 as a late stage intermedi-
ate for C-ring SAR studies is described in Scheme 2.
Treatment of 13 with DAST11 gave the difluoromethyl-
ene derivative 14, which was deprotected with aqueous
HCl to give difluoromethylene cyclopentane 2b. Rup-
pert’s reagent12 was added to the ketone of 13 to give tri-
fluoromethyl cyclopentanol 15. The tertiary alcohol of
15 was removed using Dolan and MacMillan’s13 modi-
fied Barton–McCombie14 radical deoxygenation condi-
tions. The methyl oxalyl ester of 15 was prepared
using methyl oxalyl chloride and DMAP, and was then
subjected to radical reduction initiated by AIBN and
heat in the presence of triphenyl silane. This procedure
gave a nearly 1:1 mixture of trifluoromethyl cyclopen-
tane diastereomers 16 and 17. The diastereomers were
easily separated by silica gel chromatography and then
deprotected to give the trifluoromethyl cyclopentanes
2c and 2d.15
Cyclopentanone 2a was prepared as described in Scheme
1.7 Commercially available 2,5-dimethoxycinnamic acid
(4) was treated with boron tribromide to remove the
methyl groups and promote cyclization to 6-hydroxy-
coumarin (5), which was then protected as its MOM-
ether to give 6. The Trost transition metal-catalyzed8
trimethylenemethane (TMM) cycloaddition8 was used
to install a cyclopentane ring containing an exo-methy-
lene group to give lactone 8. The exo-methylene group,
which serves as a latent ketone, was dihydroxylated with
osmium tetroxide and the resulting diol was protected as
its cyclic carbonate using phosgene to give 9. The lac-
tone 9 was deprotonated with LiHMDS and the result-
ing lactone enolate was reacted with N-phenyl
triflamide9 to give lactone enol triflate 10. Negishi’s pal-
ladium-catalyzed coupling10 conditions were used to
couple the lactone enol triflate 10 with the aryl zinc re-
agent generated from aryl lithium 18 to give the
MOM-protected 4-(4H-chromen-2-yl)phenol 11. The
enol ether of 11 was easily reduced by hydrogenation
over Pd/C to give exclusively the all cis-stereoisomer of
flavanol analog 12. At this point the latent ketone could
be revealed by hydrolyzing the cyclic carbonate of 12
with LiOH and then cleaving the diol to the ketone with
sodium periodate in the same pot. This procedure gave
MOM-protected cyclopentanone 13, which served as a
late stage intermediate for the synthesis of C-ring func-
tionalized derivatives of SERBA-1 (1a). The MOM-pro-
We wanted to compare the trifluoromethyl cyclopentane
derivatives described in Scheme 2 to the simple methyl
analog. This compound was prepared using the reduc-
tive cyclization route reported earlier5 and is described
in Scheme 3. The bis-methyl ester of commercially avail-
able (+)-3-methylhexanedioic acid (19) was prepared
using sulfuric acid and methanol. Treatment of 20 with
sodium methoxide in methanol and toluene effected a
Dieckmann cyclization to give a mixture of the 3- and
4-methyl substituted isomers of methyl 2-oxocyclopen-
tanecarboxylate (21 and 22). This mixture could not
be separated; however, when treated with triflic anhy-
dride in the presence of Hunig’s base, the 4-methyl iso-
mer was preferentially converted to enol triflate 23,
which could be easily purified by silica gel chromatogra-
phy. Enol triflate 23 was carried through the reductive
cyclization route to provide methyl cyclopentane 2e.
O
MeO
HO
RO
b
a
OH
The synthesis route that led to cyclohexanones 3a and 3b
is described in Scheme 4. The approach to cyclohexa-
none 3a utilized a Diels–Alder reaction as the key step
to install the C-ring. Beginning with hydroxy-coumarin
50%
(two steps)
OMe
O
O
O
O
O
6
4
5
TMS
c, 69%
OAc
O
7
O
e
O
O
O
H
H
H
d
RO
RO
RO
59%
H
H
HO
62%
O
CF3
O
OTf
Li
O
O
O
O
10
RO
9
8
b
c
RO
18
OR
f, 58%
44% of 16
52% of 17
O
O
O
O
O
O
13
15
OR
RO
O
(3 steps)
OR
O
g
O
a
75%
R = MOM
RO
H
RO
h
RO
F
CF3
CF3
F
83%
100%
O
O
O
RO
RO
OR
+
12
OR
11
OR
13, R = MOM
2a, R = H
i
O
O
O
OR
OR
OR
17, R = MOM
2d, R = H
Scheme 1. Coumarin route to cyclopentanone intermediate 13 for C-
ring SAR. R = MOM; Reagents and conditions: (a) BBr3, CH2Cl2, rt–
82 ꢁC; (b) MOMCl, i-Pr2EtN, CH3CN; (c) 7, Pd(OAc)2, P(OEt)3,
THF, 60 ꢁC; (d) i—OsO4, NMO, t-BuOH, H2O, THF; ii—COCl2,
Et3N, CH2Cl2, 0 ꢁC; (e) LiHMDS, THF, ꢀ78 ꢁC; PhNTf2, HMPA; (f)
i—18, ZnCl2, THF, 0 ꢁC; ii—10, Pd(PPh3)4, THF, 50 ꢁC; (g) 60 psi H2,
Pd/C, MeOH; (h) LiOH, H2O, THF; NaIO4; (i) HCl, H2O, THF.
14, R = MOM
2b, R = H
16, R = MOM
2c, R = H
d
d
d
Scheme 2. Benzopyrans prepared from ketone intermediate 13.
Reagents and conditions: (a) DAST, ClCH2CH2Cl, 40 ꢁC; (b)
TMSCF3, TBAF, THF; (c) i—ClCOCOOCH3, DMAP, Et3N,
CH2Cl2; ii—Ph3SiH, AIBN, toluene, 80 ꢁC; (d) HCl, H2O, THF.

4826
T. I. Richardson et al. / Bioorg. Med. Chem. Lett. 17 (2007) 4824–4828
Me
Suzuki coupling with 4-benzyloxyphenyl boronic acid
O
Me
Me
OMe
b
yielded the fully elaborated tetracycle 33a. Finally, joint
reduction of the enol and benzyl ethers followed by
deprotection of the ketal group afforded cyclohexanone
3a in good yield.
OR
+
RO
84%
O
OMe
O
O
a,
94%
19, R = H
O
O
22
21
20, R = Me
Me
Me
d
c, 50%
HO
The key step in forming the cyclohexanone ring of 3b in-
volved ring-closing metathesis (RCM) of an intermedi-
ate enol ether. To this end, Michael addition of allyl
magnesium bromide to 25 afforded the desired b-keto
lactone 26 containing the first RCM tether as an incon-
sequential mixture of diastereomers. A two-step saponi-
fication protocol afforded the b-allyl lactone 27. The
enol ether portion of the RCM substrate was installed
under basic conditions, alkylating with 2-O-methoxym-
ethylallyl iodide17 to yield the RCM substrate 28, which
was subjected to the second generation Grubb’s cata-
lyst18 to affect ring closure. Hydrolysis of the intermedi-
ate enol ether followed by ketal protection of the
resultant ketone afforded tricycle 29 in good yield. Con-
version of 29 to 3b followed the same route described for
3a.
OMe
O
TfO
23
O
2e
OH
Scheme 3. Synthesis of methyl analog 2e. Reagents and conditions: (a)
H2SO4, MeOH, 60 ꢁC; (b) NaOMe, MeOH, toluene, 70–110 ꢁC; (c)
Tf2O, i-Pr2EtN, CH2Cl2, ꢀ78 ꢁC; (d) reductive cyclization route.
OEt
RO
b
BnO
O
BnO
CO2Et
O
c
O
65%
72%
O
O
O
O
27
O
a,
24, R = H
25, R = Bn
26
88%
OMOM
f,
d,
BnO
BnO
64%
78%
CO2Et
O
O
O
O
30
28
e,
g,
The C-ring derivatives described above were separated
by chiral chromatography (Chiralpak AD, heptane-iso-
propanol) and evaluated for their ability to bind estro-
gen receptors a and b. SAR for the more potent
enantiomeric series is presented in Table 1.19 As can
be seen, structural variation in the C-ring of SERBA-1
(1a) had a profound impact on binding affinity and
selectivity. Although addition of a ketone at the apical
position of the cyclopentane ring (2a) resulted in a 36-
fold loss in affinity to ERb, it caused a much greater
260-fold loss in affinity to ERa. As a result, cyclopenta-
none 2a is 100-fold selective for ERb over ERa. Cyclo-
hexanones 3a and 3b demonstrate that the position of
the ketone functional group is important. Cyclohexa-
none 3a was almost devoid of affinity for either receptor
while its regioisomer 3b was nearly identical in affinity
and selectivity to cyclopentanone 2a. Although the
selectivities of the ketone analogs 2a, 3a, and 3b were
encouraging, their affinities were not competitive with
SERBA-1 (1a). We were able to improve affinity by pre-
paring fluorinated analogs 2b–d. The difluoro analog 2b
was 19-fold selective for ERb with affinity nearly identi-
cal to 1a (0.44 nM vs 0.19 nM). Both diastereomers of
the trifluoromethyl cyclopentanes 2c and 2d possessed
nearly the same selectivity for ERb as the difluoro ana-
log 2b with the endo-diastereomer 2d being slightly less
potent at both receptors. The corresponding endo-
methyl diastereomer 2e possessed affinity and selectivity
closer to SERBA-1 (1a).
64%
82%
O
O
O
O
O
BnO
BnO
O
O
O
31
29
h, 20 - 66%
O
O
O
O
i, 39 - 95%
BnO
BnO
(HO) B
2
OTf
O
33a,b
O
OBn
32a,b
OBn
j, > 95%
O
O
HO
HO
O
O
3b
3a
OH
OH
Scheme 4. Olefin metathesis and Diels–Alder routes to cyclohexanones
3a and 3b. Reagents and conditions: (a) NaH, BnBr, DMF; (b)
allylmagnesium bromide, THF, 0 ꢁC; (c) i—LiOH, THF/H2O/MeOH;
ii—o-xylenes, reflux; (d) LDA, THF, ꢀ78 ꢁC, then 2-O-methoxymeth-
ylallyl iodide; (e) i—Grubbs’ catalyst second gen (0.3 equiv), toluene;
ii—HCl, THF/H2O; iii—ethylene glycol, TsOH, toluene; (f) 2-tri-
methylsilyloxy butadiene, o-xylenes, 135 ꢁC, then pour into TBAF/
AcOH; (g) i—LiOH, THF/H2O/MeOH; ii—o-xylenes, reflux; iii—
ethylene glycol, TsOH, toluene; (h) KHMDS (3a) or LDA (3b),
PhN2Tf, HMPA/THF; (i) boronic acid, Pd(PPh3)4, LiCl, Na2CO3,
DME, reflux; (j) i—H2, Pd/C, MeOH; ii—HCl, THF/H2O.
The cocrystal structures of benzopyran 2b with ERa and
ERb are shown in Figure 2. As can be seen, the same
binding orientations are observed in these structures as
was seen in the structures of benzopyran 1a bound to
ERa and ERb, which were reported previously.5 The
D-ring phenols interact with the hydrogen bond net-
work of the Glu-Arg–H2O triad, while the A-ring phe-
nols interact with His-524 in ERa or the
corresponding His-475 in ERb. Although the two phe-
nols bind in the same places within the binding pocket,
24,16 benzyl protection of the phenol afforded benzyl
ether 25. Diels–Alder reaction with 2-trimethylsilyloxy-
butadiene under thermal conditions afforded tricycle
30. The b-keto ester was decarboxylated via a two-step
protocol, and the ketone moiety of the resultant inter-
mediate was protected as a ketal to afford 31. Conver-
sion of ester 31 to an enol triflate 32a followed by

T. I. Richardson et al. / Bioorg. Med. Chem. Lett. 17 (2007) 4824–4828
Table 1. C-ring modifications: ERa and ERb binding dataa
4827
R1
O
R2
O
HO
OH
HO
HO
OH
O
O
O
3a
1a, 2a-e
3b
OH
Compound
R1
H
R2
H
ERbb (nM)
ERab (nM)
Ratio
1a
2a
3a
3b
2b
2c
2d
2e
0.19 0.09
6.92 0.62
375 46
2.70 1.5
700 170
>1000
14
@O
101
P2.7
40
10.2
410
F
F
0.44 0.26
0.41 0.07
0.70 0.45
0.31 0.19
8.3 2.7
7.2 0.8
12.4 4.9
3.3 2.4
19
17
CF3
H
H
CF3
CH3
18
11
H
a All compounds are from the more potent enantiomeric series as drawn except 3a and 3b which are racemic.
b Ki values are means of at least two determinations SD.
Prostate Weight / Body Weight (g)
0.00055
0.00050
0.00045
0.00040
0.00035
0.00030
0.00025
0.00020
0.00015
0.00010
0.00005
0.00000
castration
intact
*
2c 1 mpk
2d 3 mpk
2c 0.3 mpk + 2d 0.3 mpk
2c 0.3 mpk + 2d 3.0 mpk
*
*
* p<0.05, compare with intact
Treatment Group
Figure 3. Effect of compounds 2c and 2d on prostate wet weight in
CD-1 mice, measured after 7 days of oral daily doses (mpk = mg/kg).
Prostate weights (PW) were normalized to body weight (BW) and the
quotient PW/BW is reported. Castrate and intact controls are also
shown. *Statistically significant (P < 0.05).
Figure 2. Diagram of the X-ray structure of the difluoro analog 2b
bound to ERa (purple) and ERb (red). The fluorine atoms are marked
with green spheres while the phenol oxygens are colored blue.
increased to 10· the dose of 2c (3.0 and 0.3 mpk, respec-
tively) the effect on prostate weight was eliminated. This
result suggests that compound 2d is able to antagonize
the effects of 2c.
the benzopyran scaffold is rotated by 180ꢁ on the bisphe-
nol axis. As a result, the difluoromethylene substituted
C-ring is pointed toward Leu-384 in ERa, but in ERb,
this ring is pointed toward Ile-373 on the other side of
the pocket. In addition, the A-ring phenol is found to
be above His-524 in ERa (as drawn in Fig. 2), while in
ERb the A-ring phenol is shifted down so that it is below
the corresponding His-475.
In summary, we were able to increase the binding selec-
tivity of the benzopyran scaffold by modifying the cyclo-
pentane C-ring of benzopyran 1a. The addition of a
ketone functional group at the apical position of the ring
significantly increased selectivity at the expense of affin-
ity. We were able to gain the affinity back and maintain
good selectivity up to 19-fold with fluorinated analogs.
The cocrystal structures of the difluoromethylene analog
2b demonstrated similar binding orientations compared
to the unfunctionalized benzopyran 1a. Although the
endo- and exo-diastereomers of the trifluoromethyl ana-
log possessed nearly identical in vitro binding profiles,
their activities in vivo were markedly different. Further
attempts to increase the selectivity of the benzopyran
scaffold will be disclosed in subsequent papers.
Although the two trifluoromethyl cyclopentane diaste-
reomers 2c and 2d possessed nearly the same in vitro
properties, their in vivo activities were quite different
(Fig. 3). We tested these compounds in a mouse model
designed to evaluate ERb agonist effects on the mouse
prostate.5 After 7 days of oral dosing at 1 mpk (mg/kg),
the exo-diastereomer of the trifluoromethyl analog (2c)
caused a significant reduction in prostate weight
compared to intact control animals. The effect of the
endo-diastereomer 2d was not statistically significant at
3 mpk. Interestingly, when the inactive diastereomer
was co-dosed with the active diastereomer, both at
0.3 mpk, a statistically significant reduction of prostate
weight was observed, but when the dose of 2d was
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