Design of a highly selective and potent class of non-planar estrogen receptorβ agonists

Article abstract of DOI:10.1002/cmdc.201300175

Selective activation of the estrogen receptorβ (ERβ) could be a safe approach to hormone replacement therapy for both women and men, in contrast to the estrogens currently used for women which activate both ERβ and ERα, occasionally causing severe side effects. The selective ERβ agonist AC-131 has shown efficacy in animal models of Parkinson's disease and neuropathic pain. With the use of AC-131 as template, herein we report the discovery, synthesis, and structure-activity relationship (SAR) study of a new class of dihydrobenzofurans as potent and selective ERβ agonists. The SAR was established by enantioselective synthesis, molecular modeling, and whole-cell-based functional assays. The most potent diastereomer, cis-10-SR, was shown to have an EC₅₀ value of <1nM, potency 100-fold higher than that of AC-131. Even more interestingly, compound trans-10-SS exhibited 1000-fold ERβ/ERα selectivity while still maintaining good potency (～10nM). In addition, trans-10-SS showed only partial agonist activity (30-60% Eff.) toward ERα at 10μM. This unprecedented selectivity could be rationalized by molecular modeling. Compound trans-10-SS appears to be the first molecule to take advantage of both conservative amino acid differences found in the α- and β-faces of the binding cavities of ERα and ERβ. Nothing flat about it: A T-shaped trans-SS diastereomer of 4-{3-fluoro-8-oxatricyclo[7.5.0.0^2,7]tetradeca-2,4,6-trien-1-yl}phenol (10) was found to be 1000-fold selective for ERβ over ERα.

Full text of DOI:10.1002/cmdc.201300175

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Nothing flat about it: A T-shaped trans-
SS diastereomer of 4-{3-fluoro-8-oxatri-
cyclo[7.5.0.02,7]tetradeca-2,4,6-trien-1-yl}-
phenol (10) was found to be 1000-fold
selective for ERb over ERa. This com-
pound exhibits ~10 nm potency and ap-
pears to be the first to take advantage
of both conservative amino acid differ-
ences found in the a- and b-faces of the
binding cavities of ERa and ERb.
H. Sundꢀn, J.-N. Ma, L. K. Hansen,
A.-L. Gustavsson, E. S. Burstein, R. Olsson*
&& – &&
Design of a Highly Selective and
Potent Class of Non-planar Estrogen
Receptor b Agonists
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DOI: 10.1002/cmdc.201300175
Design of a Highly Selective and Potent Class of Non-
planar Estrogen Receptor b Agonists
Henrik Sundꢁn,[a] Jian-Nong Ma,[b] Lars K. Hansen,[c] Anna-Lena Gustavsson,[d]
Ethan S. Burstein,[b] and Roger Olsson*[a, b, e]
Selective activation of the estrogen receptor b (ERb) could be
a safe approach to hormone replacement therapy for both
women and men, in contrast to the estrogens currently used
for women which activate both ERb and ERa, occasionally
causing severe side effects. The selective ERb agonist AC-131
has shown efficacy in animal models of Parkinson’s disease
and neuropathic pain. With the use of AC-131 as template,
herein we report the discovery, synthesis, and structure–activi-
ty relationship (SAR) study of a new class of dihydrobenzofur-
ans as potent and selective ERb agonists. The SAR was estab-
lished by enantioselective synthesis, molecular modeling, and
whole-cell-based functional assays. The most potent diastereo-
mer, cis-10-SR, was shown to have an EC50 value of <1 nm, po-
tency 100-fold higher than that of AC-131. Even more interest-
ingly, compound trans-10-SS exhibited 1000-fold ERb/ERa se-
lectivity while still maintaining good potency (~10 nm). In ad-
dition, trans-10-SS showed only partial agonist activity (30–
60% Eff.) toward ERa at 10 mm. This unprecedented selectivity
could be rationalized by molecular modeling. Compound
trans-10-SS appears to be the first molecule to take advantage
of both conservative amino acid differences found in the a-
and b-faces of the binding cavities of ERa and ERb.
Introduction
Subtype-selective estrogen receptor modulation appears to be
important in several pathological processes of neurodegenera-
tive disorders, including Parkinson’s disease (PD), Alzheimer’s
disease (AD), multiple sclerosis, and amyotrophic lateral sclero-
sis.[1] In most of these diseases, aging is the major risk factor,
and the diseases occur around the point in life when bioavail-
able endogenous sex steroid levels in plasma are generally de-
creasing.[2] Mechanistically, the protective effects of estrogens
have been linked to stabilization of mitochondria by protection
against oxidative stress.[3] In addition, estrogens regulate en-
zymes that catabolize proteins which aggregate in AD and PD,
such as insulin-degrading enzyme and cathepsin D, which de-
grade the Ab-peptide and a-synuclein, respectively.[4] Further-
more, estrogen signaling plays an essential role in modulating
neuroplasticity and cognition.[5]
The therapeutic use of the endogenous estrogen 17b-estra-
diol (E2) (Figure 1), which potently activates both nuclear ERa
and ERb, is limited by its feminizing effects and an increased
risk of cancer.[6] However, these side effects are believed to be
associated with activation of ERa. Thus, compounds selective
for ERb could potentially be used safely for chronic treatment
in both men and women.
[a] Dr. H. Sundꢀn, Prof. R. Olsson
Department of Chemistry & Molecular Biology
University of Gothenburg, Kemivꢁgen 10, 41296 Gothenburg (Sweden)
E-mail: roger.olsson@chem.gu.se
[b] Dr. J.-N. Ma, Dr. E. S. Burstein, Prof. R. Olsson
ACADIA Pharmaceuticals Inc.
3911 Sorrento Valley Blvd., San Diego, CA 92121 (USA)
[c] Prof. L. K. Hansen
Department of Chemistry, Faculty of Science & Technology
University of Tromsø, 9037 Tromsø (Norway)
[d] Dr. A.-L. Gustavsson
Chemical Biology Consortium Sweden, Department of Medical
Biochemistry & Biophysics, Science for Life Laboratory
Karolinska Institutet, 17177 Stockholm (Sweden)
[e] Prof. R. Olsson
Chemical Biology & Therapeutics
Department of Experimental Medical Science
Lund University, Sçlvegatan 19, 22184 Lund (Sweden)
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/cmdc.201300175.
Figure 1. Estrogen receptor agonists.
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In 2008, we reported on a nonsteroidal selective ERb ago-
nist, AC-131, (Figure 1) and evaluated this molecule in several
pain animal models involving nerve injury or sensitization and
chronic inflammatory pain.[7] AC-131 alleviated tactile hyperal-
gesia induced by capsaicin and reversed tactile allodynia
caused by spinal nerve ligation and various chemical insults.
Moreover, AC-131 did not influence the pain threshold of
normal healthy animals. AC-131 was further evaluated in an
animal model of PD induced through bilateral 6-hydroxydopa-
mine lesions of the substantia nigra. In this model, AC-131 pre-
vented motor, cognitive, and sensorimotor gating deficits and
mitigated the loss of dopamine neurons in the substantia
nigra. Interestingly, in male rats, E2 did not show the same
neuroprotective benefits as the selective ERb agonist, AC-
131.[1d] Hence, in addition to a beneficial safety profile, a selec-
tive ERb agonist could have a different pharmacological profile
from that of the nonselective E2. A further indication of this is
the identification of two endogenous ligands, 5-androsten-
3b,17b-diol and 5a-andostane-3b,17b-diol, which activate ERb
(Figure 1).[1c]
phenols are potent ERb agonists (Figure 2). However, the initial
synthesis we used was laborious (seven steps), time consum-
ing, and generated isomeric mixtures, diastereomers, and
enantiomers, which had to be separated by crystallization,
chiral preparative HPLC, or both.[10] To establish an SAR profile
and to synthesize larger quantities for in vivo evaluation, we
needed to find an enantioselective convergent synthesis of the
three-membered benzofuran core, including the formation of
two consecutive stereogenic centers, one of which is an all-
carbon quaternary center.[11] Moreover, from extensive SAR
studies in the AC-131 series, we established that compounds
containing halogens in the cycloalkyl and non-phenolic aryl
rings, as well as the size of the cycloalkyl ring, gave the most
interesting ligands; therefore, reaction conditions to introduce
and preserving these functionalities had to be taken into ac-
count.
An asymmetric route to synthesize the tricyclic dihydroben-
zofuran motif was designed that could be used for both scaf-
folds. The key intermediates, allylic alcohols 4a–c (Scheme 1),
A common method to make compounds more potent is to
increase their rigidity. The two compounds SERM-b 1[8] and 8b-
VE2[9] are examples of potent and rigid ERb-selective agonists.
Hence, connecting one of the aryl rings with the cyclohexyl
moiety of AC-131 could potentially form at least two rigid tri-
cyclic compounds (Figure 2). Basic molecular modeling indicat-
Scheme 1. Asymmetric synthesis of allylic alcohols 4a–d. Reagents and con-
ditions: a) 2a: I2, DMAP, 82%, RT, 16 h; b) 2b: I2, pyridine, 89%, 08C!RT,
16 h; c) Pd/C, Na2CO3, ArB(OH)2, 808C, 15 min, 3a: 83%, 3b: 91%, 3c: 75%,
3d: 83%; d) (S)-CBS, borane dimethyl sulfide complex, 08C!RT, 4 h, 4a:
83%, 98% ee, 4b: 86%, 96% ee, 4c: 89%, 84% ee; e) CeCl3·7H2O, NaBH4,
4d: 80%, 08C, 20 min.
Figure 2. Connection of the cyclohexyl group in AC-131 with one of the aryl
moieties generates two different scaffolds: benzofuranol and benzofuran-
phenol.
ed that both the benzofuranol and the benzofuran-phenol had
reasonable overlays with other non-planar ERb agonists, imply-
ing that both could potentially modulate ERb. Therefore, both
compounds were synthesized. However, biological evaluation
showed that only the benzofuran-phenols were active at ERb.
Herein we describe the enantioselective synthesis and biologi-
cal evaluation, including the establishment of an SAR profile,
of a new class of selective ERb agonists based on a benzofur-
an-phenol scaffold.
were synthesized. The first step involved the amine-catalyzed
iodo-Baylis–Hillman reaction of a,b-unsaturated ketones, pro-
ducing iodo-carbonyls 2a–b in 82–89% yield.[12] Iodo-carbonyls
2a–b were easily functionalized through a Pd/C-catalyzed
Suzuki reaction to efficiently produce aryl ketones 3a–d in 75–
91% yield.[13] The aryl ketones 3a–c were subjected to asym-
metric oxaborolidine-catalyzed reduction to give cyclic allylic
alcohols 4a–c in high yields and high enantiomeric excess. For
example, (S)-CBS catalyzed the reduction of ketones 3a and 3c
to yield the (R)-alcohols 4a and 4c in 98% ee and 84% ee, re-
spectively. The other enantiomers were obtained using the (R)-
CBS catalyst.[14]
Results and Discussion
In the development of next-generation ERb agonists based on
AC-131, we envisioned that connecting one of the aryl rings
with the cyclohexane, creating two stereogenic centers, would
yield a rigid scaffold which, in addition to being more potent
and selective, would simplify the establishment of an SAR pro-
file. It was discovered that optically pure dihydrobenzofuran-
Having established a highly enantioselective and robust
method, the cyclic allylic alcohols were further reacted using
a Mitsunobu reaction with a set of different iodophenols 5a–f
to yield ethers 6a–g (Scheme 2).[15] Next, a palladium-catalyzed
intramolecular Mizoroki–Heck coupling using Pd(OAc)2, PPh3,
and Ag2CO3 converted ethers 6a–g to the cis-fused tricyclic
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were also synthesized. Notably,
the use of H2 and Pd/C was not
suitable for the reduction of aryl
chloride-containing olefins be-
cause the reduction of 7c–
e yielded partial or complete de-
halogenation. However, using
Rh/C provided a selective and
high-yielding reduction of the
double bond in 92–95% yields,
with only trace amounts of de-
halogenation. Finally, the tert-bu-
tyldimethylsilyl (TBS) protecting
group was quantitatively re-
moved by TBAF to give 8c–f.
The cis-fused ring system was
determined by NOESY NMR ex-
periments, and X-ray crystallog-
raphy (Figure 3) verified the ab-
solute configuration of com-
pound 8c.[17]
Scheme 2. Synthesis of benzofurans 8a–g. Reagents and conditions: a) DIAD, PPh3, toluene, 08C!RT, 6a: 60%,
6b: 56%, 6c: 87%, 6d: 71%, 6e: 85%, 6 f: 72%, 6g: 63%; b) Pd(OAc)2, PPh3, Ag2CO3, 808C, 16 h, 7a: 95%, 7b:
72%, 7c: 85%, 7d: 92%, 7e: 79%, 7 f: quant; c) Pd/C, H2; RT, overnight, d) H-Cube, Rh/C, 208C; e) TBAF, RT, over-
night, 8a: 67%, 8b: 55%, 8c: 61%, 8d: 69%, 8e: 48%, 8 f: 39%, 8g: 15%.
The synthesis of compounds
16 and 18 started with sequen-
benzofurans 7a–f in high isolated yields as the sole diastereo-
meric products. However, in a few cases, trace amounts of
a double bond isomer were present in a crude NMR sample.
Interestingly, when conducting the Heck reaction with the
larger cycloheptenyl 9, a 1:1 mixture of diastereomers was iso-
lated in 72% yield (Scheme 3). The 1:1 trans/cis ratio of 9 is be-
Figure 3. ORTEP rendering of compound 8c.
Scheme 3. Synthesis of benzofurans trans-10-SS and cis-10-SR. Reagents and
conditions: a) Pd(OAc)2, PPh3, Ag2CO3, 72%; b) Pd/C, H2, 79% (diastereomers
separated by recrystallization).
tial protection of benzophenone 11 to yield the orthogonally
protected 11 (Scheme 4). Treatment of 12 with MeMgBr, fol-
lowed by acid-mediated elimination, gave 13. Hydroboration
of 13 rendered the terminal alcohol, which was oxidized with
DMP to give aldehyde 14 in 47% yield over three steps. Benzo-
furan 15 was synthesized from 14 (32% yield) by a one-pot
quadruple cascade Michael-Robinson-deprotection-oxo-Mi-
chael-addition sequence and was isolated as the cis-fused dia-
lieved to be the result of the higher flexibility of the cyclohep-
tenyl relative to the cyclohexenyl. In the subsequent step, the
benzofuran double bond and the benzyl protecting group
were removed by Pd/C under a hydrogen atmosphere to yield
the desired dihydrobenzofurans 8a, 8b, 8g,[16] and 10. The
trans-10-SS/cis-10-SR mixture was separated by recrystallization
from methanol. By analogy, the trans-10-RR/cis-10-RS isomers
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of 5.7 and 70% efficacy at ERa (Table 1, entry 3). Introducing
a halogen on the aryl moiety (substituent Y) generally im-
proved activity; for example, compounds 8b–e with a halogen
substituent at the 3- or 4-position exhibited increased activity
relative to 8a (Table 1, entries 3–6). It should be noted that the
potency gradually decreased as the halogen substituent was
moved from the 3-position to the 4-position and finally to the
5-position. For example, 8c with a chloro in the 3-position was
40 times more potent than 8 f with the chloro in the 5-posi-
tion. In addition, compound 8c showed nearly 160-fold selec-
tivity for ERb over ERa. Fluoro-substituted 8b was less active
than 8c, indicating that the size, electronegativity, or both
properties of the aryl substituents are important for potency.
Introducing a carbonyl (16), by analogy, to SERM-b 1 did not
provide the intended interaction and was equipotent with 8a.
Transforming the polar ketone to gem-difluoro compound 18
increased the activity over 16 and 8a. This may be related to
an increase in the steric bulk of the cyclohexyl moiety. More-
over, a clear SAR was established for the two scaffolds, i.e.,
benzofuranol 8g and benzofuran-phenol 8b, with only the
latter scaffold showing activity. To exclude the possibility that
this lack of activity occurred by chance, eight analogues of 8g
were synthesized. However, none of these showed any activity
at ERb (data not shown). The highest activity was observed for
cycloheptyl derivative cis-10-SR, with a pEC50 value of 9.5 and
80-fold selectivity for ERb over ERa. The larger cycloheptyl
moiety resulted in more active compounds. This trend was
also observed in difluorobenzofuran 18, indicating that
a larger and flexible ring can adopt conformations important
for selectivity and activity.
Scheme 4. Synthesis of benzofurans 16 and 18. Reagents and conditions:
a) BnBr, K2CO3; b) (4-methoxyphenyl)methanol, DEAD, PPh3; c) MeMgBr, HCl
(2m); d) BH3, NaOH (6m), H2O2; e) DMP, 47%; f) methyl vinyl ketone, KOH
(3m), 32%; g) Pd/C (10%)/H2, 16: 60%, 18: 26%; h) diethylaminosulfur tri-
fluoride 52%.
stereomer. Treatment of compound 15 with diethylaminosulfur
trifluoride (DAST) gave a mixture of gem-difluoro species 17
and traces of vinyl fluoride in 52% crude yield. Finally, after
Pd/C-catalyzed hydrogenolysis of the benzyl, 16, and 18 could
be isolated in 60 and 26% yields, respectively.
All compounds were evaluated in vitro using the proprietary
mammalian cell-based functional assay R-SAT (receptor selec-
tion and amplification technology), a reporter gene assay, or
both (see Supporting Information for details).[18] In general, the
compounds were highly active at ERb and showed high selec-
tivity over ERa, acting as partial or full agonists with efficacies
ranging from 80–134%. Unsubstituted compound 8a has
a pEC50 value of 7.7 and efficacy of 121% at ERb and a pEC50
Interestingly, when examining the different cycloheptyl iso-
mers, enantiomer cis-10-SR was 40-fold more active than its
enantiomer cis-10-RS. Both trans-fused diastereomers (trans-
10-SS and trans-10-RR) were less active than the most potent
cis isomer, but were still quite potent, with pEC50 values of 8.1
Table 1. In vitro results for ERb agonists in R-SAT and reporter gene assays.[a]
Entry
Ligand
R-SAT
Reporter Gene Assay
Selectivity[b]
ERa
ERb
ERa
ERb
pEC50
Eff. [%]
pEC50
Eff. [%]
pEC50
Eff. [%]
pEC50
Eff. [%]
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
E2
AC-131
8a
8b
8c
8d
8e
8 f
8g
9.8
4.7
5.5
–
–
–
–
–
–
<5
5.3
<5
<5
7.1
5.0
100
63
61
–
–
–
–
–
–
43
70
30
45
107
83
10.2
7.2
7.6
–
–
–
–
–
–
6.7
8.0
7.6
7.4
9.3
7.6
100
90
78
–
–
–
–
–
–
87
89
80
59
91
101
9.6
ND
5.7
6.3
6.7
6.7
6.0
<5
5.2
5.0
5.5
5.1
<5
7.6
5.6
100
ND
70
61
62
66
62
37
109
52
73
60
42
68
62
10.0
7.5
7.7
8.3
8.9
8.5
7.9
7.3
–
7.6
8.4
8.1
7.3
9.5
7.9
100
119
121
134
118
127
109
89
21
110
98
98
128
90
–
316/–
126/100
–/100
–/158
–/63
–/79
–/631
–
>50/398
501/794
>398/1000
>251/>200
158/80
398/158
16
18
trans-10-SS
trans-10-RR
cis-10-SR
cis-10-RS
118
[a] See the Supporting Information for a detailed description of the R-SAT and reporter gene assays.[18] Agonist efficacies were compared with that of E2;
values represent the mean of two or more independent experiments, with each experiment performed at eight doses in triplicate. Standard deviation
values for all measurements can be found in the Supporting Information. [b] Selectivity for ERb over ERa in R-SAT and the reporter gene assay.
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ies.[19,20] The phenol in all four isomers of 10 interacts with
Glu305, Arg346, and water, making the hydrogen bonding
network important for obtaining agonist activity. After initial
docking, the predicted binding poses were post-processed and
minimized with the LBD of ERb, allowing the amino acid side
chains to move around the ligand within a 4 ꢃ distance. The
relative calculated MM-GBSA DGbind was evaluated and com-
pared with the biological activities. Although it is difficult to
use a whole cell functional assay in quantitative evaluations
because of the many factors that can influence potency, the
calculations correlated well with the in vitro results.[21]
In the predicted models (Figure 5a–d), the cycloheptyl
moiety for all of the isomers is positioned in the same area as
the cyclohexenyl group of SERM-b 1, while the benzofuran
part projects into the a-face cavity, as observed for the butyl
chain of SERM-b 1. Strikingly, depending on the isomer, the cy-
cloheptyl occupies more of the b-face of the LBD to different
degrees than does the cyclohexyl of SERM-b 1. The most
potent compound, cis-10-SR (pEC50 9.5), had the most favora-
ble binding energy in the docking studies (Figure 5a). The
other three isomers (pEC50 ~8) had 2–4 kcalmolꢀ1 higher calcu-
lated binding energies. Co-crystals with the non-planar ligands
(i.e., SERM-b 1) showed a high degree of flexibility of side
chains in the LBD. In the a-face, Phe377 is shifted, thereby
opening a binding pocket and allowing the butyl chain of the
Figure 4. Receptor activity for a) cis-10-SR and b) trans-10-SS. Data are nor-
malized to the response of 17b-estradiol; *: ERb, *: ERa.
and 7.3, respectively (Table 1, en-
tries 11 and 12). More interest-
ingly, trans-10-SS was highly se-
lective at ERb (1000ꢂ) and only
a partial agonist at ERa at con-
centrations
(Figure 4).
up
to
10 mm
ERa and ERb have two conser-
vative amino acid differences in
the ligand binding domain (LBD;
Figure 5). In the b-face of the
LBD residue, Leu384 in ERa is re-
placed with Met336, while
Met421 in ERa is replaced with
Ile373 in ERb. These small differ-
ences in the LBD make it difficult
to achieve selectivity between
the two receptors.[19] Several co-
crystal structures have been re-
ported for both ERa and ERb.
For ERb, co-crystals have been
reported both with planar li-
gands that mimic E2 and non-
planar ligands such as SERM-
b 1.[8b] The non-planar ligands
have shown a higher degree of
selectivity between the two nu-
Figure 5. The co-crystal structures of SERM-b 1 (gray) and ERb (2GIU.pdb, gray residues) overlaid with ERa
(1ERE.pdb, red residues). Only important amino acids are shown. a) Proposed binding mode of the most active
enantiomer, compound cis-10-SR (light blue), based on docking to 2GIU.pdb. b) Proposed binding mode of both
clear estrogen receptors. The cis-fused enantiomers of 10, cis-10-SR (light blue) and the less active cis-10-RS (purple). c) cis-10-SR (light blue), as
well as the less active trans-fused diastereomers trans-10-SS (dark green) and trans-10-RR (light green). The rigidity
non-planar shape of compounds
and more pronounced T-shape of the trans isomers cause the compounds to protrude into the a-face of the LBD
10 made it reasonable to use
as well as into the b-face. d) SERM-b 1 (gray) and the most selective compound, trans-10-SS (dark green). With-
the SERM-b 1 co-crystal structure
drawal of trans-10-SS from the Glu305/Arg346 residue results in lower potency but also closer proximity to
(2GIU.pdb) in our docking stud- Met336; this may explain the increased selectivity.
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ene or THF. Toluene and THF were freshly distilled from benzophe-
SERM-b 1 to take its place in proximity to Ile373. These interac-
tions in the a-face appear to explain the selectivity for ERb. An-
other strategy was used in the design of the ERb selective
ligand 8b-VE2.[19] In contrast to SERM-b 1, the selectivity of 8b-
VE2 is proposed to result from extension into the b-face,
where the vinyl group experiences steric repulsion with the
Leu384 in ERa. This does not occur to the same degree with
Met336 in ERb (thoroughly discussed elsewhere).[19] The less
potent cis isomer, cis-10-RS, which has an aromatic benzofuran
moiety perpendicular toward the edge of Phe356, does not in-
teract favorably with the accessible pocket (Figure 5b). The
highly ERb-selective benzofuran trans-10-SS has a benzofuran
group in the a-face of the pocket close to Ile373, similar to
SERM-b 1. The cycloheptyl group occupies the b-face of the
pocket close to the second amino acid Met336, causing the
phenol to slightly withdraw from Glu305/Arg346 (Figure 5c,d).
This causes a gain in selectivity but a loss in potency relative
to cis-10-SR. The selectivity can potentially be attributed to
steric repulsion in the ERa with Leu384, similar to 8b-VE2, and
a favorable interaction in the a-face, similar to SERM-b 1.
Hence, trans-10-SS combines the selectivity features of SERM-
b 1 and 8b-VE2.
1
none/sodium. H and 13C NMR spectra were recorded in CDCl3 on
a JEOL JNM-EX 400 spectrometer at 400 and 100 MHz, respectively,
while 13C NMR spectra were recorded on a 500 Varian Unity Inova
spectrometer at 126 MHz. Chemical shifts are reported in ppm,
with the solvent residual peak as an internal standard (CHCl3 d=
7.26 ppm, CDCl3 d=77.0 ppm). 19F NMR was measured with ethyl
trifluoroacetate as an internal standard (ꢀ75.8 ppm) and recorded
at 376 MHz on a Varian 400 MHz spectrometer equipped with
a Varian OneNMRProbe with a proton observation frequency of
399.95 MHz. The reactions were monitored by thin layer chroma-
tography (TLC) on silica-plated aluminum sheets (silica gel 60 F254,
Merck) detecting spots by UV (254 and 365 nm) and cerium molyb-
date. Flash chromatography was performed on Merck silica gel 60
(0.040–0.063 mm). Optical rotation was measured on a PerkinElmer
polarimeter 341 LC. Gas chromatography/mass spectrometry analy-
ses were performed on a Varian Saturn 2000 GC–MS with a Supelco
SLB-5ms fused silica capillary column using helium as carrier gas;
injector temperature: 3008C; temperature program: 70 to 3308C
(128Cminꢀ1); hold time: 4 min. The MS detector consisted of an
ion trap with 70 eV ionization. Chiral HPLC chromatography analy-
ses were performed on a Varian 9012Q/9050 UV/Vis detector using
HPLC-grade solvents (n-hexane and 2-propanol). Purity (>98%)
was measured at 254 nm on a Waters 2690/996 photodiode array
detector using HPLC-grade solvents (H2O/0.1% TFA:CH3CN/0.1%
TFA) with an Atlantis T3 5 mm, 4.6ꢂ250 mm column. Prep HPLC
was done on a Waters 600/2487 dual l absorbance detector using
HPLC-grade solvents; H2O/0.1% TFA:CH3CN/0.1% TFA with an At-
lantis prep T3 5 mm, 19ꢂ250 mm column. HRMS was measured on
a Thermo LTQ-OrbitrapXL nano-ES in positive ion mode.
Conclusions
Selectivity between the two nuclear estrogen receptors is of
major concern in using estrogens for chronic treatments, as ac-
tivation of ERa might lead to severe side effects. We therefore
designed a class of highly selective and potent ERb agonists
based on benzofurans as a new molecular scaffold. The com-
pounds presented display a preference for ERb over ERa and
are more active than the parent compound, AC-131. We devel-
oped an asymmetric synthesis approach that facilitated investi-
gation of the enantiomers and found cis-10-SR to be the most
active compound. More interestingly, the most selective mole-
cule, trans-10-SS, showed a 1000-fold preference for ERb over
ERa and retained very good potency. Based on the predicted
binding mode using computational chemistry, we speculate
that this is the first ligand to take advantage of the two con-
servative amino acid differences between ERa and ERb to ach-
ieve selectivity. Molecular modeling showed that the T-shaped
topology of trans-10-SS protrudes into the a- and b-faces to
gain selectivity at ERb but at the expense of loss in activity rel-
ative to cis-10-SR. Moreover, our SAR study showed that substi-
tution in the 3-position of the aromatic benzofuran is impor-
tant for biological activity and that cis-fused seven-membered
rings are more active than smaller six-membered rings. Overall,
we have shown that the rigid benzofuran motif is an excellent
scaffold to gain high ERb selectivity and constitutes a good
starting point for further development of safe estrogenic treat-
ments.
(4-((tert-Butyldimethylsilyl)oxy)phenyl)boronic acid: Siloxyphenyl
bromide (11.0 g, 38 mmol) was dissolved in THF (70 mL, freshly dis-
tilled). The solution was purged with argon and cooled to ꢀ758C
in a CO2/acetone bath. N-Butyllithium (2.5m in hexanes, 28 mL)
was added slowly while maintaining the temperature below
ꢀ658C. A white precipitate formed during the addition. The mix-
ture was stirred for 1 h below ꢀ658C, then trimethyl borate
(26.5 mL, 115 mmol) was added while maintaining the temperature
at ꢀ658C. The resulting clear solution was warmed to room tem-
perature and stirred for 16 h. Concentrated HCl was added until
the mixture reached pH 6–7. The reaction mixture was poured into
Et2O (500 mL), and the aqueous layer was discarded. The organic
layer was washed three times with H2O, dried over anhydrous
MgSO4, and filtered. The solvent was removed, and the product
was recrystallized from EtOAc/pentane to yield the product as an
1
off-white solid in 68% yield (6.6 g): H NMR (400 MHz, CDCl3): d=
8.13 (d, J=7.8 Hz, 2H), 6.97 (d, J=7.3 Hz, 2H), 1.03 (s, 9H),
0.27 ppm (s, 6H); 13C NMR (101 MHz, CDCl3): d=159.7, 137.4, 119.8,
99.9, 25.7, 18.3, ꢀ4.3 ppm.
2-(4-((tert-Butyldimethylsilyl)oxy)phenyl)cyclohex-2-enone (3b):
General procedure A: DME (6 mL) and H2O (6 mL) were added to
a 20 mL microwave vial containing 2a, (668 mg, 3.0 mmol), Na2CO3
(637 mg, 6.0 mmol), Ar-B(OH)2 (1517 mg, 6 mmol), and Pd/C
(160 mg, 5 mol%). The mixture was degassed by alternating
vacuum and N2 three times, pre-stirred for 5 min, and then subject-
ed to microwave irradiation at 808C for 15 min. Without removing
the microwave cap, the reaction mixture was extracted with Et2O
(5ꢂ5 mL), and the organic phase was dried over (Na2SO4), evapo-
rated, and purified by flash chromatography (5:1, pentane/EtOAc)
Experimental Section
1
General: Chemicals and solvents were purchased from Sigma–Al-
drich. Reactions involving oxygen- or moisture-sensitive reagents
were carried out under nitrogen atmosphere using anhydrous tolu-
to afford the aryl ketone in 91% yield (824 mg): H NMR (400 MHz,
CDCl3): d=7.20 (d, J=8.7 Hz, 2H), 6.98 (t, J=4.3 Hz, 1H), 6.80 (d,
J=8.7 Hz, 2H), 2.60–2.55 (m, 2H), 2.53–2.48 (m, 2H), 2.14–2.02 (m,
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2H), 0.99 (s, 9H), 0.20 ppm (s, 6H); 13C NMR (101 MHz, CDCl3): d=
198.3, 155.2, 147.0, 139.7, 129.6, 129.5, 119.5, 39.1, 26.6, 25.6, 22.9,
18.1, ꢀ4.5 ppm; MS (EI): m/z (%): 302 [M]+ (100), 247 (14), 246 (35),
245 (31), 217 (23).
(S)-2-(4-(Benzyloxy)phenyl)cyclohept-2-enol: Following general
procedure B, the title compound was obtained after silica gel chro-
matography in 99% yield (400 mg) and 87% ee.
2-(2-Fluorophenyl)cyclohex-2-en-1-ol (4d): General procedure C:
3d (190 mg, 1 mmol) and CeCl3·7H2O (360 mg, 1 mmol) were dis-
solved in 1 mL MeOH. NaBH4 (76 mg, 2 mmol) was added dropwise
as a MeOH solution (2 mL) while stirring at 08C. The reaction was
monitored by TLC and quenched with 2m HCl, and the mixture
was extracted with ether, dried over Na2SO4, and concentrated in
vacuo. Purification by flash chromatography (pentane/EtOAc, 5:1)
afforded the title compound as a white solid in 80% yield
(154 mg): 1H NMR (400 MHz, CDCl3): d=7.29 (td, J=7.7, 1.8 Hz,
1H), 7.21 (dddd, J=8.1, 7.1, 5.1, 1.8 Hz, 1H), 7.09 (td, J=7.5, 1.3 Hz,
1H), 7.02 (ddd, J=11.0, 8.2, 1.2 Hz, 1H), 5.98 (t, J=3.9 Hz, 1H), 4.59
(t, J=3.8 Hz, 1H), 2.27–2.13 (m, 2H), 1.97–1.87 (m, 1H), 1.86–1.75
(m, 2H), 1.72–1.60 ppm (m, 1H); 13C NMR (101 MHz, CDCl3): d=
159.8 (d, J=245.8 Hz), 136.1 (d, J=1.9 Hz), 131.4 (d, J=2.6 Hz),
130.3 (d, J=4.4 Hz), 128.6 (d, J=14.3 Hz), 128.3 (d, J=8.3 Hz),
123.9 (d, J=3.5 Hz), 115.4 (d, J=23.0 Hz), 66.4 (d, J=3.4 Hz), 31.5,
25.7, 17.8 ppm.
2-(4-(Benzyloxy)phenyl)cyclohept-2-enone (3c): Following gener-
al procedure A, the title compound was obtained after silica gel
chromatography as an off-white solid in 75% yield (121 mg):
1H NMR (400 MHz, CDCl3): d=7.49–7.30 (m, 5H), 7.21 (d, J=8.8 Hz,
2H), 6.92 (d, J=8.8 Hz, 2H), 6.70 (t, J=6.5 Hz, 1H), 5.06 (s, 2H),
2.72 (dd, J=7.3, 5.8 Hz, 2H), 2.51 (dd, J=12.0, 6.3 Hz, 2H), 1.97–
1.72 ppm (m, 4H); 13C NMR (101 MHz, CDCl3): d=205.9, 158.3,
144.1, 140.4, 137.0, 131.6, 129.2, 128.6, 127.9, 127.4, 114.5, 70.0,
43.1, 28.0, 24.9, 22.2 ppm.
2-(2-Fluorophenyl)cyclohex-2-en-1-one (3d): Following general
procedure A, purification by flash chromatography (5:1, pentane/
EtOAc) afforded the title compound as a white solid in 83% yield
1
(355 mg): H NMR (400 MHz, CDCl3): d=7.31–7.23 (m, 1H), 7.16 (td,
J=7.4, 2.0 Hz, 1H), 7.13–6.98 (m, 3H), 2.57 (t, J=6.7 Hz, 2H), 2.50
(td, J=6.0, 4.3 Hz, 2H), 2.15–2.02 ppm (m, 2H); 13C NMR (101 MHz,
CDCl3): d=196.3, 159.6 (d, J=247.0 Hz), 149.7 (s), 135.7 (d, J=
1.0 Hz), 130.8 (d, J=3.9 Hz), 129.1 (d, J=8.2 Hz), 124.3 (d, J=
15.8 Hz), 123.4 (d, J=3.6 Hz), 115.1 (d, J=22.3 Hz), 38.1, 26.0,
22.5 ppm.
(S)-1-(4-(Benzyloxy)phenyl)-7-(3-chloro-2-iodophenoxy)cyclohex-
1-ene (6c): General procedure D: DIAD (1.03 mL, 6.99 mmol) was
added to a stirred solution of 4b (1120 mg, 3.68 mmol), 3-chloro-2-
iodophenol (1872 mg, 7.35 mmol), and PPh3 (1929 mg, 7.35 mmol)
in toluene (50 mL) at 08C. The solution was stirred overnight, then
diluted with toluene (50 mL) and quenched with NaOH (4 mL, 1m).
The organic layer was separated, washed with H2O (5 mL) and
brine (5 mL), dried over MgSO4, and concentrated. The crude prod-
uct was purified by flash chromatography (20:1, pentane/EtOAc) to
render the product as white crystals in 87% yield (100 mg) and
(R)-2-(4-((tert-Butyldimethylsilyl)oxy)phenyl)cyclohex-2-enol
(4b): General procedure B: A pre-stirred (10 min, RT) solution of
(S)-(ꢀ)-2-methyl-CBS-oxazaborolidine (357 mg, 1.29 mmol) and
borane dimethyl sulfide complex (BMS) (2.36 mL, 4.72 mmol, 2m
solution) in toluene, 30 mL was placed in an ice bath. To the cold
reaction mixture was then added a solution of 2-(4-((tert-butyldi-
methylsilyl)oxy)phenyl)cyclohex-2-enone (1300 mg, 4.30 mmol in
toluene, 40 mL) via a syringe pump over 2 h. The reaction was con-
tinued for a further 2 h at 08C before being quenched with HCl
(1m, 2 mL), diluted with Et2O (10 mL), extracted, washed with H2O
(10 mL) and brine (10 mL), and dried over MgSO4. The crude prod-
uct was purified by silica gel chromatography (gradient: pentane
! pentane/EtOAc, 1:6) to give the title compound in 86% yield
(1100 mg) and 96% ee: 1H NMR (400 MHz, CDCl3): d=7.35 (d, J=
8.6 Hz, 2H), 6.81 (d, J=8.6 Hz, 2H), 6.09 (dd, J=4.7, 3.3 Hz, 1H),
4.67 (t, J=3.8 Hz, 1H)), 2.29–2.07 (m, 2H), 2.00–1.91 (m, 1H), 1.88–
1.71 (m, 3H), 1.71–1.60 (m, 1H), 1.00 (s, 9H), 0.21 ppm (s, 6H);
13C NMR (101 MHz, CDCl3): d=154.9, 138.3, 133.1, 127.1, 126.9,
120.0, 65.3, 31.5, 26.0, 25.6, 18.2, 17.2, ꢀ4.5 ppm; ½aꢁ2D0 = +61.0
(c=1, CHCl3); HPLC: Diacel Chiralpak AD column, n-hexane/2-prop-
anol (99:1), flow rate: 1 mLminꢀ1, l=254 nm, tR =11.2 min (minor)
and 12.7 min (major). The racemate was prepared by reducing
ketone following general procedure C (see synthesis of 4d below):
MS (EI): m/z (%): 304 [M]+ (100), 289 (14), 288 (12), 287 (40), 249
(13), 248 (19), 247 (43), 231 (14), 230 (31), 229 (22), 181 (12), 155
(16), 153 (15).
1
88% ee: mp: 120.8–122.48C; H NMR (400 MHz, CDCl3): d=7.17 (d,
J=8.6 Hz, 2H), 7.10 (t, J=8.1 Hz, 1H), 6.97 (dd, J=8.0, 1.1 Hz, 1H),
6.68 (dt, J=5.1, 3.0 Hz, 3H), 6.21 (dd, J=5.0, 2.8 Hz, 1H), 5.09 (s,
1H), 2.41–2.26 (m, 1H), 2.18–2.02 (m, 2H), 1.99–1.83 (m, 1H), 1.71–
1.51 (m, 2H), 0.91 (s, 9H), 0.11 ppm (s, 6H); 13C NMR (101 MHz,
CDCl3): d=158.4, 154.7, 139.9, 134.9, 134.1, 129.8, 129.5, 126.8,
121.6, 119.8, 110.7, 93.4, 73.8, 27.4, 25.8, 25.6, 18.1, 17.1, ꢀ4.5 ppm;
½aꢁ2D0 =ꢀ6.4 (c=1, CHCl3); HPLC: Diacel Chiralpak AD column, n-
hexane/2-propanol (9:1), flow rate: 1 mLminꢀ1, l=254 nm, tR =
10.2 min (major) and 12.2 min (minor).
(S)-1-(4-(Benzyloxy)phenyl)-7-(5-chloro-2-iodophenoxy)cyclohex-
1-ene (6e): Following general procedure D, the title compound
was obtained after silica gel chromatography as a colorless oil in
1
85% yield (602 mg) and 83% ee: H NMR (400 MHz, CDCl3): d=7.64
(d, J=8.4 Hz, 1H), 7.21 (d, J=8.7 Hz, 2H), 6.88 (d, J=2.2 Hz, 1H),
6.74 (d, J=8.7 Hz, 2H), 6.69 (dd, J=8.3, 2.2 Hz, 1H), 6.28 (dd, J=
5.0, 2.9 Hz, 1H), 5.13 (t, J=3.0 Hz, 1H), 2.43–2.30 (m, 1H), 2.26–2.11
(m, 2H), 2.03–1.88 (m, 1H), 1.80–1.68 (m, 2H), 0.96 (s, 9H),
0.17 ppm (s, 6H); 13C NMR (101 MHz, CDCl3): d=157.4, 154.8, 140.0,
134.9, 134.9, 134.1, 130.0, 126.9, 122.5, 119.9, 114.1, 85.6, 73.9, 27.5,
25.8, 25.7, 18.2, 17.1, ꢀ4.4 ppm; ½aꢁ2D0 =ꢀ50.4 (c=6.15, CHCl3);
HPLC: Diacel Chiralpak AD column, n-hexane/2-propanol (9:1), flow
rate: 1 mLminꢀ1, l=254 nm, tR =8.0 min (major) and 11.0 min
(minor).
(R)-2-(4-(Benzyloxy)phenyl)cyclohept-2-enol (4c): Following gen-
eral procedure B, the title compound was obtained after silica gel
chromatography in 89% yield (447 mg) and 84% ee: 1H NMR
(400 MHz, CDCl3): d=7.48–7.24 (m, 7H), 7.03–6.87 (m, 2H), 5.97 (dt,
J=8.1, 1.8 Hz, 1H), 5.06 (s, 2H), 4.77 (dd, J=7.7, 2.0 Hz, 1H), 2.48–
2.35 (m, 1H), 2.29–2.18 (m, 1H), 2.12–1.94 (m, 2H), 1.93–1.51 ppm
(m, 4H); 13C NMR (101 MHz, CDCl3): d=157.7, 145.6, 137.0, 135.4,
130.8, 128.5, 127.9, 127.9, 127.4, 114.5, 72.7, 69.9, 33.7, 27.5, 26.7,
25.0, 15.9 ppm; HPLC: Diacel Chiralpak AD column, n-hexane/2-
propanol (95:5), flow rate: 1 mLminꢀ1, l=254 nm, tR =17.3 min
(minor) and 19.7 min (major).
(S)-1-(4-(Benzyloxy)phenyl)-7-(4-chloro-2-iodophenoxy)cyclohex-
1-ene (6d): Following general procedure D, the title compound
was obtained after silica gel chromatography as a colorless oil in
1
71% yield (235 mg) and 75% ee: H NMR (400 MHz, CDCl3): d=7.72
(d, J=2.6 Hz, 1H), 7.24–7.18 (m, 3H), 6.80 (d, J=8.8 Hz, 1H), 6.74
(d, J=8.6 Hz, 2H), 6.27 (dd, J=5.0, 2.9 Hz, 1H), 5.11 (t, J=3.2 Hz,
1H), 2.46–2.34 (m, 1H), 2.26–2.07 (m, 2H), 2.04–1.90 (m, 1H), 1.78–
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1.61 (m, 2H), 0.97 (s, 9H), 0.17 ppm (s, 6H); 13C NMR (101 MHz,
CDCl3): d=155.7, 154.7, 138.7, 135.0, 134.1, 129.9, 129.0, 126.9,
126.2, 119.9, 114.1, 88.5, 74.0, 27.5, 25.8, 25.7, 18.2, 17.1, ꢀ4.4 ppm;
½aꢁ2D0 =ꢀ32.4 (c=1, CHCl3); HPLC: Diacel Chiralpak AD column, n-
hexane/2-propanol (9:1), flow rate: 1 mLminꢀ1, l=254 nm, tR =
9.3 min (major) and 13.5 min (minor).
heated at 808C for 16 h. The reaction mixture was filtered through
a plug of Celite, concentrated, and purified by silica gel chroma-
tography (pentane/EtOAc, 20:1) to yield the cyclic product as a col-
1
orless oil in 85% yield (96 mg): H NMR (400 MHz, CDCl3): d=7.20–
7.07 (m, 4.7H, overlapping), 6.84–6.71 (m, 5.9H overlapping), 6.12–
6.06 (m, 0.5H, minor), 6.06–6.03 (m, 2H), 5.93–5.86 (m, 0.1H,
minor), 4.80 (dd, J=4.8, 4.0 Hz, 0.3H, minor), 4.75 (t, J=2.9 Hz,
1H), 3.03–2.74 (m, 0.2H, minor), 2.58–2.38 (m, 0.2H, minor), 2.38–
2.25 (m, 1H), 2.23–2.00 (m, 2H), 1.85–1.72 (m, 1H), 0.98 (s, 9H),
0.97 (s, 3.3H, minor), 0.20 (s, 6H), 0.19 ppm (s, 2.0H, minor);
13C NMR (101 MHz, CDCl3): d=161.4, 161.2, 154.6, 154.2, 137.7,
136.3, 133.0, 131.2, 131.0, 130.8, 129.7, 129.6, 128.8, 128.5, 128.2,
128.0, 126.7, 125.1, 122.2, 122.1, 119.9, 119.9, 108.7, 108.3, 91.3,
90.1, 54.0, 31.3, 28.0, 25.8, 25.8, 21.6, 19.1, 18.6, 18.3, 18.3,
ꢀ4.3 ppm; ½aꢁ2D0 = +14.0 (c=1, CHCl3); MS (EI): m/z (%): 415 [M+
H]+ (13), 414 [M]+ (44), 413 [M+H]+ (100), 360, (10), 359 (25), 358
(10), 357 (11), 207 (12), 205 (14), 205 (35).
(S)-1-(4-(Benzyloxy)phenyl)-7-(3-fluoro-2-iodophenoxy)cyclohex-
1-ene (6b): Following general procedure D, the title compound
was obtained after silica gel chromatography as a colorless oil in
56% yield (100 mg): 1H NMR (400 MHz, CDCl3): d=7.42–7.30 (m,
5H), 7.28 (d, J=8.4 Hz, 2H), 7.24–7.16 (m, 1H), 6.86 (d, J=8.5 Hz,
2H), 6.70–6.59 (m, 2H), 6.27 (dd, J=5.0, 2.8 Hz, 1H), 5.16 (t, J=
2.5 Hz, 1H), 5.01 (s, 2H), 2.45–2.33 (m, 1H), 2.26–2.09 (m, 2H),
2.02–1.87 (m, 1H), 1.77–1.59 ppm (m, 2H); 13C NMR (101 MHz,
CDCl3): d=163.0 (d, J=244.2 Hz), 158.5 (d, J=5.7 Hz), 157.9, 137.0,
134.9, 133.9, 130.0, 129.9 (d, J=9.9 Hz), 128.5, 127.9, 127.4, 127.0,
114.6, 108.8 (d, J=2.8 Hz), 108.2, 107.9, 73.8, 69.9, 27.5, 25.9,
17.1 ppm.
tert-Butyl(4-[(1R,9S)-5-chloro-8-oxatricyclo[7.4.0.02,7]trideca-
2(7),3,5,12-tetraen-1-yl]phenoxy) dimethylsilane (7e): Following
the general procedure E, the title compound was isolated after
silica gel chromatography as a colorless oil in 79% yield (120 mg).
1H NMR (400 MHz, CDCl3): d=7.18 (d, J=8.5 Hz, 2H), 6.86–6.83 (m,
3H), 6.79 (d, J=8.4 Hz, 2H), 5.96 (ddd, J=10.0, 5.5, 2.1 Hz, 7H),
5.63 (d, J=10.1 Hz, 1H), 4.74 (t, J=1.6 Hz, 1H), 2.38–2.25 (m, 7H),
2.19–1.99 (m, 2H), 1.83–1.72 (m, 7H), 0.98 (s, 9H), 0.20 ppm (s, 6H);
13C NMR (101 MHz, CDCl3): d=160.8, 154.7, 136.3, 133.6, 133.4,
129.3, 129.2, 127.0, 125.3, 121.0, 119.8, 110.7, 90.5, 52.9, 25.6, 21.5,
18.9, 18.2, ꢀ4.4 ppm; ½aꢁ2D0 = +11.8 (c=1, CHCl3); MS (EI): m/z (%):
415 [M+H]+ (15), 414 [M]+ (45), 413 [M+H]+ (34), 412 (100), 384
(11), 271 (10), 209 (26), 205 (29), 177 (10).
(S)-1-(4-(Benzyloxy)phenyl)-7-(3-fluoro-2-iodophenoxy)cyclo-
hept-1-ene (6g): Following general procedure D, the title com-
pound was isolated after silica gel chromatography as an off-white
solid in 63% yield (0.454 mg) and 73% ee. Optical purity was in-
1
creased to 95% ee after recrystallization in toluene/MeOH: H NMR
(400 MHz, CDCl3): d=7.48–7.30 (m, 5H), 7.18 (d, J=8.9 Hz, 2H),
7.04 (td, J=8.3, 6.7 Hz, 1H), 6.90 (d, J=8.9 Hz, 2H), 6.60 (ddd, J=
8.4, 7.5, 1.1 Hz, 1H), 6.30 (d, J=8.4 Hz, 1H), 6.15 (dd, J=8.0, 6.1 Hz,
1H), 5.27 (d, J=6.9 Hz, 1H), 5.06 (s, 2H), 2.85–2.73 (m, 1H), 2.49–
2.18 (m, 3H), 2.02–1.79 (m, 3H), 1.69–1.55 ppm (m, 1H); 13C NMR
(101 MHz, CDCl3): d=164.8 (d, J=243.7 Hz), 161.5, 158.1 (d, J=
5.8 Hz), 157.7, 142.2, 137.0, 135.8, 134.2, 129.8 (d, J=9.8 Hz), 129.8
(d, J=9.8 Hz), 128.6, 127.9, 127.5, 127.0, 114.6, 108.8 (d, J=2.7 Hz),
107.7 (d, J=24.3 Hz), 79.2, 75.1 (d, J=26.3 Hz), 70.0, 31.2, 27.3,
26.7, 26.0 ppm; HPLC: Diacel Chiralpak AD column, n-hexane/2-
propanol (97:3), flow rate: 1 mLminꢀ1, l=254 nm, tR =5.7 min
(major) and 6.2 min (minor).
tert-Butyl(4-[(1R,9S)-4-chloro-8-oxatricyclo[7.4.0.02,7]trideca-
2(7),3,5,12-tetraen-1-yl]phenoxy) dimethylsilane (7d): Following
general procedure E, the title compound was isolated after silica
gel chromatography as a colorless oil in 92% yield (112 mg):
1H NMR (400 MHz, CDCl3): d=7.21 (d, J=8.4 Hz, 2H), 7.12 (ddd, J=
8.5, 2.3, 0.6 Hz, 1H), 6.94 (d, J=2.3 Hz, 1H), 6.82 (d, J=8.4 Hz, 2H),
6.77 (d, J=8.5 Hz, 1H), 6.00 (ddd, J=9.8, 5.4, 1.9 Hz, 1H), 5.66 (d,
J=10.1 Hz, 1H), 4.75 (t, J=9.8, 1.82 Hz, 1H), 2.40–2.27 (m, 1H),
2.21–2.02 (m, 2H), 1.86–1.68 (m, 1H), 1.00 (s, 9H), 0.23 ppm (s, 6H);
13C NMR (101 MHz, CDCl3): d=158.6, 154.7, 136.5, 136.1, 129.2,
129.1, 128.2, 127.2, 125.4, 124.8, 119.8, 110.9, 90.3, 53.5, 25.6, 21.4,
18.9, 18.2, ꢀ4.4 ppm; ½aꢁ2D0 = +31.3 (c=1, CHCl3); MS (EI): m/z (%):
415 [M+H]+ (12), 414 [M]+ (38), 413 [M+H]+ (32), 412 (89), 177
(19).
(R)-1-(4-(benzyloxy)phenyl)-7-(3-fluoro-2-iodophenoxy)cyclo-
hept-1-ene: Following general procedure D, the title compound
was isolated after silica gel chromatography as an off-white solid,
69% yield (513 mg) and 71% ee.
1-{6-[5-(Benzyloxy)-2-iodophenoxy]cyclohex-1-en-1-yl}-2-fluoro-
benzene (6 f): Following general procedure D, the title compound
was obtained after silica gel chromatography (heptane/toluene,
5:1) as a colorless oil in 72% yield (285 mg): 1H NMR (400 MHz,
CDCl3): d=7.57 (d, J=8.6 Hz, 1H), 7.45–7.35 (m, 5H), 7.25–7.18 (m,
1H), 7.10 (td, J=7.5, 1.2 Hz, 1H), 7.02 (ddd, J=10.9, 8.2, 1.1 Hz,
1H), 6.54 (d, J=2.6 Hz, 1H), 6.36 (dd, J=8.6, 2.7 Hz, 1H), 6.19 (d,
J=3.9 Hz, 1H), 5.22 (t, J=3.6 Hz, 1H), 4.98 (s, 2H), 2.45–2.35 (m,
1H), 2.31–2.21 (m, 1H), 2.16–1.98 (m, 2H), 1.97–1.86 (m, 1H), 1.78–
1.67 ppm (m, 1H); 13C NMR (101 MHz, CDCl3): d=160.1, 159.9 (d,
J=243.2 Hz) 158.6, 157.6, 139.0, 136.5, 133.7 (d, J=2.0 Hz), 132.8
(d, J=1.2 Hz), 130.9 (d, J=4.2 Hz), 129.0 (d, J=14.2 Hz), 128.5,
128.4 (d, J=8.3 Hz), 128.0, 127.4, 124.0 (d, J=3.4 Hz), 115.2 (d, J=
22.8 Hz), 108.4, 102.2, 77.3, 74.2 (d, J=3.3 Hz), 70.1, 27.7, 25.7,
17.5 ppm.
(2R,7S)-2-[4-(benzyloxy)phenyl]-13-fluoro-8-oxatricy-
clo[7.4.0.02,7]trideca-1(9),3,10,12-tetraene (7b): Following general
procedure E, the title compound was obtained and used without
further purification in the next step.
1-[4-(Benzyloxy)phenyl]-3-fluoro-8-oxatricy-
clo[7.5.0.02,7]tetradeca-2,4,6,13-tetraene (9): Following general
procedure E, the title compound was isolated after silica gel chro-
matography as a colorless oil in a 72% yield (119 mg), and 1:1 dia-
stereomeric ratio: 1H NMR (400 MHz, CDCl3): d=7.48–7.27(m, 4H,
major, 4H minor), 7.23–7.07 (m, 1H major, 1H minor), 6.96 (d, J=
8.9 Hz, 2H major), 6.89 (d, J=8.9 Hz, 2H minor), 6.80–6.50 (m, 2H
major, 2H minor), 6.17–5.86 (m, 2H major, 2H minor), 5.06 (s, 2H
(major)), 5.03 (s, 2H (minor)), 5.00 (dd, J=12.2, 5.2 Hz, 1H (minor)),
4.81 (dd, J=8.8, 2.2 Hz, 1H (major)), 2.34–2.06 (m, 4H major, 4H
minor), 2.04–1.80 (m, 2H major, 2H minor), 1.75–1.65 (m, 1H
major, 1H minor), 1.62–1.43 ppm (m, 1H major, 1H minor);
13C NMR (101 MHz, CDCl3): d=160.8 (d, J=9.3 Hz), 160.4 (d, J=
tert-Butyl(4-[(1R,9S)-3-chloro-8-oxatricyclo[7.4.0.02,7]trideca-
2(7),3,5,12-tetraen-1-yl]phenoxy) dimethylsilane (7c): General
procedure E: a solution of aryl ether 6c (148 mg, 0.27 mmol) in tol-
uene (20 mL) was added to a 20 mL microwave vial containing
Ag2CO3 (226 mg, 0.82 mol), PPh3 (21 mg, 0.082 mmol), and
Pd(OAc)2 (9.2 mg, 0.04 mmol). The vial was sealed, and the reaction
mixture was evacuated and flushed with nitrogen three times and
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8.9 Hz), 159.1 (d, J=248.8 Hz), 158.9 (d, J=248.7 Hz), 157.7, 157.6,
137.2, 137.0, 133.5, 133.0, 131.3 (d, J=3.6 Hz), 130.51, 130.48, 129.9
(d, J=9.0 Hz), 129.5 (d, J=8.8 Hz), 128.9, 128.8, 128.5, 128.5,
127.91, 127.90, 127.7, 127.5, 127.5, 124.3 (d, J=18.1 Hz), 120.9 (d,
J=17.3 Hz), 114.7, 114.2, 108.8 (d, J=20.7 Hz), 108.2 (d, J=
20.8 Hz), 106.6 (d, J=3.4 Hz), 105.9 (d, J=3.4 Hz), 94.1, 91.3, 70.0,
69.9, 59.1 (d, J=3.0 Hz), 56.7 (d, J=2.7 Hz), 28.8, 28.1, 27.4, 26.6,
20.6, 19.8 ppm; 19F NMR (376 MHz, CDCl3): d=ꢀ75.80 (s), ꢀ118.25
(dd, J=9.4, 5.8 Hz), ꢀ120.95 ppm (dd, J=9.3, 5.7 Hz).
11-(Benzyloxy)-2-(2-fluorophenyl)-8-oxatricyclo[7.4.0.02,7]trideca-
1(9),3,10,12-tetraene (7 f): Following general procedure E, the title
compound could not be sufficiently purified by silica gel chroma-
tography and was therefore used without further purification in
the next step.
raphy (gradient: 10:1–5:1, pentane/EtOAc) and then C18 prepara-
tive chromatography ((H2O, 0.1% TFA)/(CH3CN/H2O, 95:5, 0.1%
TFA), gradient: 0!100%), at 15 mLminꢀ1 to give the title com-
pound as a white solid in 71% yield (46 mg): 1H NMR (400 MHz,
CDCl3): d=7.25 (d, J=6.8 Hz, 1H), 7.07 (dd, J=8.2, 7.8 Hz, 1H),
6.81–6.78 (m, 1H), 6.77 (d, J=8.0 Hz, 1H), 4.75 (t, J=3.1 Hz, 1H),
4.65 (s, 1H), 2.63–2.49 (m, 1H), 2.11–1.88 (m, 1H), 1.67–1.57 ppm
(m, 5H); 13C NMR (101 MHz, CDCl3): d=160.2, 154.0, 136.0, 134.5,
130.5, 129.2, 128.8, 122.2, 115.1, 108.6, 90.9, 51.9, 30.0, 25.3, 20.8,
18.6 ppm; ½aꢁ2D0 =ꢀ12.6 (c=1, CHCl3); MS (EI): m/z (%): 302 [M]+
(37), 301 [M]+ (23), 300 [M]+ (100), 259 (18), 258 (21), 257 (45), 154
(11), 160 (10), 159 (12); HRMS-ESI: m/z [M+H]+ calcd for
C18H18ClO2: 301.0995, found: 301.0988.
4-[(1R,9S)-3-Chloro-8-oxatricyclo[7.4.0.02,7]trideca-2(7),3,5,12-tet-
raen-1-yl]phenol (8d): Following general procedure G, the title
compound was isolated after C18 preparative chromatography
((H2O, 0.1%TFA)/(CH3CN/H2O, 95:5, 0.1% TFA) gradient: 0!100%)
tert-Butyl(4-[(1R,9S)-3-chloro-8-oxatricyclo[7.4.0.02,7]trideca-
2(7),3,5-trien-1-yl]phenoxy) dimethylsilane: General procedure F:
7c in EtOH was subjected to hydrogen cube-mediated reduction
conditions using Rh/C (0.5 mLminꢀ1, 208C, full H2-mode). The reac-
tion mixture was looped until full conversion was observed by GC–
MS (approximately seven loops). The saturated title compound
was isolated in 92% yield (92 mg): 1H NMR (400 MHz, CDCl3): d=
7.22 (d, J=8.6 Hz, 2H), 7.06 (t, J=8.0 Hz, 1H), 6.84–6.68 (m, 4H),
4.77 (t, J=3.0 Hz, 1H), 2.63–2.51 (m, 1H), 2.11–1.98 (m, 1H), 1.97–
1.83 (m, 1H), 1.76–1.45 (m, 5H), 0.98 (s, 9H), 0.19 ppm (s, 6H);
13C NMR (101 MHz, CDCl3): d=160.5, 154.2, 136.5, 134.9, 130.6,
129.2, 128.7, 122.2, 119.8, 108.6, 91.0, 52.0, 30.2, 25.8, 25.4, 20.9,
18.8, 18.3, ꢀ4.3 ppm; ½aꢁ2D0 =ꢀ9.5 (c=1, CHCl3); MS (EI): m/z (%):
416 [M]+ (43), 415 [M]+ (34), 414 [M]+ (100), 360 (12), 359 (21), 358
(31), 357 (31), 209 (24), 208 (15), 207 (53), 179 (15), 125 (10).
1
at 15 mLminꢀ1 as a clear oil in 69% yield (5 mg): H NMR (400 MHz,
CDCl3): d=7.18 (d, J=8.6 Hz, 1H), 7.10 (t, J=8.0 Hz, 1H), 6.85–6.78
(m, 3H), 6.75 (d, J=8.0 Hz, 1H), 6.10–5.99 (m, 2H), 4.72 (t, J=
2.9 Hz, 1H), 2.41–2.24 (m, 1H), 2.19–2.01 (m, 2H), 1.84–1.71 ppm
(m, 1H); 13C NMR (101 MHz, CDCl3): d=161.3, 154.3, 135.9, 130.91,
130.85, 129.6, 129.0, 128.3, 126.5, 122.1, 115.2, 108.7, 90.0, 53.9,
21.4, 18.9 ppm; HRMS-ESI: m/z [M+H]+ calcd for C18H16ClO2:
299.0839, found: 299.0822.
4-[(1R,9S)-5-Chloro-8-oxatricyclo[7.4.0.02,7]trideca-2(7),3,5-trien-
1-yl]phenol (8 f): Following general procedure G, the title com-
pound was isolated after C18 preparative chromatography ((H2O,
0.1%TFA)/(CH3CN/H2O, 95:5, 0.1% TFA) gradient: 0!100%) at
1
15 mLminꢀ1 as a clear oil in 41% yield (3 mg): H NMR (400 MHz,
tert-Butyl(4-[(1R,9S)-5-chloro-8-oxatricyclo[7.4.0.02,7]trideca-
2(7),3,5-trien-1-yl]phenoxy)dimethylsilane: Following general
procedure F, the title compound was isolated after silica gel chro-
matography as a colorless oil in 95% yield (10 mg): 1H NMR
(400 MHz, CDCl3): d=7.18 (d, J=8.7 Hz, 2H), 6.81 (ddd, J=26.0,
11.0, 4.7 Hz, 5H), 4.86 (t, J=4.1 Hz, 1H), 2.28 (dd, J=14.5, 6.9 Hz,
1H), 2.03–1.91 (m, 1H), 1.82–1.69 (m, 3H), 1.68–1.47 ppm (m, 3H);
13C NMR (101 MHz, CDCl3): d=159.7, 154.2, 136.9, 136.7, 133.1,
128.4, 124.3, 120.8, 119.7, 110.8, 90.7, 50.6, 33.7, 26.1, 25.7, 21.3,
19.4, 18.2, ꢀ4.4 ppm; ½aꢁ2D0 =ꢀ18.7 (c=1, CHCl3); MS (EI): m/z (%):
416 [M]+ (41), 415 [M]+ (33), 414 [M]+ (100), 360 (12), 359 (7), 358
(20), 209 (11), 207 (20), 179 (11).
CDCl3): d=7.20 (d, J=8.8 Hz, 2H), 6.89–6.67 (m, 5H), 4.84 (t, J=
4.1 Hz, 1H), 2.32–2.19 (m, 1H), 2.04–1.92 (m, 1H), 1.82–1.46 ppm
(m, 6H); 13C NMR (101 MHz, CDCl3): d=159.6, 154.0, 136.8, 136.4,
133.2, 128.7, 124.2, 120.8, 115.1, 110.9, 90.7, 50.6, 33.6, 26.1, 21.3,
19.4 ppm; ½aꢁ2D0 =ꢀ27.6 (c=0.38, CHCl3); MS (EI): m/z (%): 302 [M]+
(35), 301 [M]+ (24), 300 [M]+ (100), 259 (35), 258 (18), 257 (92), 222
(15), 194 (10); HRMS-ESI: m/z [M+H]+ calcd for C18H18ClO2:
301.0995, found: 301.0988.
4-[(1R,9S)-4-Chloro-8-oxatricyclo[7.4.0.02,7]trideca-2(7),3,5-trien-
1-yl]phenol (8e): Following general procedure G, the title com-
pound was isolated after C18 preparative chromatography ((H2O,
0.1%TFA)/(CH3CN/H2O 95:5, 0.1% TFA)) gradient: 0!100%),
tert-Butyl(4-[(1R,9S)-4-chloro-8-oxatricyclo[7.4.0.02,7]trideca-
2(7),3,5-trien-1-yl]phenoxy) dimethylsilane: Following general
procedure F, the title compound was isolated after silica gel chro-
matography as a colorless oil in 95% yield (10 mg): 1H NMR
(400 MHz, CDCl3): d=7.20 (d, J=8.7 Hz, 2H), 7.08 (dd, J=8.4,
2.3 Hz, 1H), 6.82–6.74 (m, 4H), 4.85 (t, J=3.9 Hz, 1H), 2.29 (dd, J=
9.3, 5.1 Hz, 1H), 2.00 (dd, J=14.0, 3.9 Hz, 1H), 1.81–1.49 ppm (m,
6H); 13C NMR (101 MHz, CDCl3): d=157.5, 154.3, 140.4, 136.1,
128.5, 127.7, 125.4, 123.8, 119.8, 111.0, 90.3, 51.2, 33.8, 26.0, 25.7,
21.4, 19.5, 18.2, ꢀ4.4 ppm; ½aꢁ2D0 = +27.5 (c=1, CHCl3); MS (EI): m/z
(%): 416 [M]+ (43), 415 [M]+ (35), 414 [M]+ (100), 360 (8), 359 (12),
358 (17), 209 (9), 207 (27), 179 (12).
1
15 mLminꢀ1 as a clear oil in 51% yield (3.7 mg): H NMR (400 MHz,
CDCl3): d=7.23 (d, J=8.9 Hz, 2H), 7.08 (dd, J=8.4, 2.3 Hz, 1H),
6.83–6.75 (m, 4H), 4.85 (t, J=3.9 Hz, 1H), 2.36–2.23 (m, 1H), 2.07–
1.96 (m, 1H), 1.84–1.47 ppm (m, 6H); 13C NMR (101 MHz, CDCl3):
d=157.4, 154.1, 147.4, 140.3, 128.8, 127.8, 123.8, 115.2, 111.1, 99.9,
90.4, 51.1, 33.7, 26.0, 21.4, 19.5 ppm; ½aꢁ2D0 = +24.5 (c=0.4, CHCl3);
MS (EI): m/z (%): 302 [M]+ (35), 301 [M]+ (22), 300 [M]+ (100), 259
(19), 258 (11), 257 (52), 194 (16), 145 (10); HRMS-ESI: m/z [M+H]+
calcd for C18H18ClO2: 301.0995, found: 301.0979.
4-[(1R,9S)-3-Fluoro-8-oxatricyclo[7.4.0.02,7]trideca-2(7),3,5-trien-1-
yl]phenol (8b): General procedure H: 7b (36 mg, 0.097 mmol) was
dissolved in EtOH (5 mL), followed by addition of Pd/C (10 mg,
10% wt). The reaction was purged three times by alternating
vacuum and H2, after which the reaction mixture stirred overnight
(16 h) under an atmosphere of H2. The mixture was filtered
through a pad of Celite, concentrated, and purified by silica gel
chromatography to yield a white solid in 55% yield (15 mg):
1H NMR (400 MHz, CDCl3): d=7.23 (d, J=8.7 Hz, 2H), 7.12 (td, J=
8.1, 5.8 Hz, 1H), 6.78 (d, J=8.8 Hz, 2H), 6.65 (d, J=8.0 Hz, 1H), 6.55
4-[(1R,9S)-3-Chloro-8-oxatricyclo[7.4.0.02,7]trideca-2(7),3,5-trien-
1-yl]phenol (8c): General procedure G: TBAF (1m) was added to
a
vial
containing
tert-butyl(4-[(1R,9S)-3-chloro-8-oxatricy-
in
clo[7.4.0.02,7]trideca-2(7),3,5-trien-1-yl]phenoxy)dimethylsilane
THF (5 mL). The reaction was stirred overnight and quenched with
1 mL H2O. Et2O (20 mL) was added, and the organic layer was
washed with H2O and brine, dried over MgSO4, and concentrated
in vacuo. The crude product was purified by silica gel chromatog-
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(t, J=8.8 Hz, 1H), 4.88 (s, 1H), 4.83 (t, J=4.5 Hz, 1H), 2.31 (d, J=
5.0 Hz, 1H), 2.13 (d, J=7.6 Hz, 1H), 1.99–1.75 (m, 2H), 1.74–
1.39 ppm (m, 4H); 13C NMR (101 MHz, CDCl3): d=161.1 (d, J=
9.2 Hz), 159.5 (d, J=247.9 Hz), 154.1, 137.2, 129.6 (d, J=8.8 Hz),
128.0, 122.3 (d, J=18.0 Hz), 115.2, 108.2 (d, J=20.9), 106.3, 90.5,
51.5, 31.8, 26.2, 20.9, 18.9 ppm; 19F NMR (376 MHz, CDCl3): d=
ꢀ75.8 (s), ꢀ120.2 ppm (dd, J=9.2, 5.8 Hz). ½aꢁ2D0 =ꢀ6.0 (c=1,
CHCl3); MS (EI): m/z (%): 285 [M]+ (35), 284 [M]+ (100), 242 (10),
241 (48), 191 (20); HRMS-ESI: m/z [M+H]+ calcd for C19H20FO2:
285.1291, found: 285.1283.
2-{[4-(Benzyloxy)phenyl]carbonyl}phenol: 4-[(2-Hydroxyphenyl)-
carbonyl]phenol (3 g, 14 mmol), benzyl bromide (1.7 mL,
14.1 mmol), and K2CO3 (3.9 g, 28 mmol) were stirred at reflux over-
night in CH3CN (30 mL). The reaction mixture was filtered through
Celite and evaporated. The crude mixture was purified by silica gel
chromatography to yield the title compound in 54% yield (2.3 g):
1H NMR (400 MHz, CDCl3): d=11.97 (s, 1H), 7.72 (d, J=8.8 Hz, 2H),
7.64 (dd, J=8.0, 1.7 Hz, 1H), 7.52–7.34 (m, 5H), 7.08 (d, J=8.9 Hz,
3H), 6.92–6.86 (m, 1H), 5.17 ppm (s, 2H); 13C NMR (101 MHz,
CDCl3): d=200.0, 162.9, 162.0, 136.1, 135.8, 133.2, 131.8, 130.5,
128.7, 128.2, 127.5, 119.3, 118.5, 118.3, 114.5, 70.2 ppm.
4-{3-Fluoro-8-oxatricyclo[7.5.0.02,7]tetradeca-2,4,6-trien-1-yl}phe-
nol (10): Following general procedure H, the title compound was
purified by silica gel chromatography to yield a white solid in 79%
yield (147 mg). The diastereomers were separated by dissolving
the white solid in MeOH (1.5 mL) and separating the mother liquor
(dr2, cis-10-SR) from the remaining white solid (dr1, trans-10-SS).
This procedure was repeated until a diastereomerically pure com-
pound could be observed.
[4-(Benzyloxy)phenyl]({2-[(4-methoxyphenyl)methoxy]phenyl})-
methanone (12): (4-Methoxyphenyl)methanol (2.1 g, 15.6 mmol),
PPh3 (3.4 g, 13 mmol), 2-{[4-(benzyloxy)phenyl]carbonyl}phenol
(4 g, 13 mmol), THF (20 mL), and DEAD (5.9 mL, 13 mmol, 40% in
toluene) were added to a flask and stirred at room temperature.
The reaction was quenched after 16 h, concentrated, and purified
using silica gel chromatography (pentane/EtOAc, 20:1–5:1–3:1) to
yield compound 12: 1H NMR (400 MHz, CDCl3): d=7.80 (d, J=
8.8 Hz, 1H), 7.49–7.32 (m, 2H), 7.09–6.93 (m, 2H), 6.76 (d, J=
8.7 Hz, 1H), 5.12 (s, 2H), 4.96 (s, 2H), 3.76 ppm (s, 3H); 13C NMR
(101 MHz, CDCl3): d=195.2, 162.6, 159.1, 156.1, 136.2, 132.1, 131.4,
131.3, 129.9, 129.4, 128.6, 128.6, 128.4, 128.2, 127.4, 120.8, 114.3,
113.7, 113.1, 70.1, 70.0, 55.2 ppm.
1
trans-10-SS: Mp: 275–2778C; H NMR (400 MHz, CDCl3): d=7.34 (d,
J=8.8 Hz, 2H), 7.02 (td, J=8.2, 5.7 Hz, 1H), 6.72 (d, J=8.9 Hz, 2H),
6.64 (d, J=8.0 Hz, 1H), 6.42 (dd, J=9.3, 8.5 Hz, 1H), 4.94 (dd, J=
11.5, 6.2 Hz, 1H), 4.59 (s, 1H), 3.34–3.21 (m, 1H), 2.32–2.07 (m, 2H),
2.00–1.77 (m, 3H), 1.72–1.58 (m, 2H), 1.51–1.40 (m, 1H), 1.04–
0.81 ppm (m, 1H); 13C NMR (101 MHz, [D6]DMSO): d=159.7 (d, J=
9.8 Hz), 158.3 (d, J=246.1 Hz), 155.7, 131.1, 129.5 (d, J=8.8 Hz),
127.3, 126.4 (d, J=18.4 Hz), 115.0, 108.1 (d, J=20.9 Hz), 106.6, 91.9,
53.4, 32.6, 26.7, 25.7, 24.2, 22.5 ppm; ½aꢁ2D0 = +189.0 (c=1, EtOAc);
MS (EI): m/z (%): 299 [M]+ (22), 298 [M]+ (100), 241 (40), 205 (17);
19F NMR (376 MHz, [D6]DMSO): d=ꢀ75.8 (s), ꢀ121.0 ppm (dd, J=
9.4, 6.0 Hz); HRMS-ESI: m/z [M+H]+ calcd for C19H20FO2: 299.1447,
found: 299.1440.
1-(1-(4-(Benzyloxy)phenyl)vinyl)-2-((4-methoxybenzyl)oxy)ben-
zene (13): MeMgBr (16.6 mmol, 3m) was added to a stirred solu-
tion of 12 (4.7 g, 11 mmol) in THF at 08C; this was allowed to
reach RT, was stirred for 72 h, and was quenched with 2m HCl, ex-
tracted with Et2O (2ꢂ50 mL), dried over Na2SO4, and reduced in va-
cuo. The title compound was difficult to purify and was therefore
used without further purification in the next reaction.
2-(4-(Benzyloxy)phenyl)-2-(2-((4-methoxybenzyl)oxy)phenyl)e-
thanol: BF3 (16.4 mL, 1m in THF) was added to a stirred solution of
13 (3.5 g, 8.2 mmol) in THF (20 mL) at 08C until complete conver-
sion of the alkene was observed by TLC. The mixture was again
cooled to 08C before subsequent addition of H2O in THF (10%),
NaOH (6m, 13.7 mL), and H2O2 (10.6 mL) and allowed to reach RT.
The mixture was stirred overnight, after which the mixture was ad-
justed to ~pH 2 with HCl (2m) and extracted with Et2O, dried over
MgSO4, and evaporated. The title compound was difficult to purify
and was used without further purification in the next reaction.
1
cis-10-SR: Mp: 156.4–159.18C; H NMR (400 MHz, CDCl3): d=7.20–
7.14 (m, 1H), 7.11 (d, J=8.4 Hz, 2H), 6.75 (d, J=8.8 Hz, 2H), 6.64
(dd, J=8.0, 0.5 Hz, 1H), 6.56 (t, J=9.0 Hz, 1H), 4.90 (dd, J=6.6,
1.6 Hz, 1H), 4.66 (s, 1H), 2.40–2.26 (m, 2H), 2.19 (dt, J=12.9, 5.2 Hz,
1H), 1.90–1.79 (m, 1H), 1.75–1.53 (m, 4H), 1.43–1.28 (m, 1H), 1.18–
1.04 ppm (m, 1H); 13C NMR (101 MHz, CDCl3): d=161.2 (d, J=
9.7 Hz), 159.5 (d, J=248.2 Hz), 153.9 (s), 140.6 (s), 130.1 (d, J=
9.1 Hz), 127.1 (s), 119.6 (d, J=18.0 Hz), 115.3 (s), 107.6 (d, J=
21.0 Hz), 105.4 (d, J=3.3 Hz), 95.1 (d, J=0.8 Hz), 57.4 (d, J=2.9 Hz),
36.3 (d, J=1.3 Hz), 31.3, 31.1, 25.7, 23.1 ppm; ½aꢁ2D0 = +15.2 (c=1,
CHCl3); MS (EI): m/z (%): 299 [M]+ (21), 298 [M]+ (100), 242 (12),
241 (51); 19F NMR (376 MHz, CDCl3): d=ꢀ75.8 (s), ꢀ117.9 ppm (s);
HRMS-ESI: m/z [M+H]+ calcd for C19H20FO2: 299.1447, found:
299.1441.
2-(4-(Benzyloxy)phenyl)-2-(2-((4-methoxybenzyl)oxy)phenyl)ace-
taldehyde (14): 2-(4-(Benzyloxy)phenyl)-2-(2-((4-methoxybenzyl)ox-
y)phenyl)ethanol (2.8 g, 6.2 mmol) dissolved in CH2Cl2 (1 mL) was
added to
a stirred solution of Dess–Martin reagent (3.4 g,
8.1 mmol) in CH2Cl2 (40 mL) and left to stir for 16 h. The suspension
was then evaporated and directly purified by silica gel chromatog-
raphy to yield aldehyde 14 in 47% yield (2.3 g) over three steps:
1H NMR (400 MHz, CDCl3): d=9.79 (d, J=1.3 Hz, 1H), 7.35–7.20 (m,
5H), 7.15–7.11 (m, 3H), 7.01 (d, J=8.7 Hz, 2H), 6.95 (dd, J=7.5,
1.6 Hz, 1H), 6.88 (d, J=8.3 Hz, 1H), 6.85 (d, J=8.7 Hz, 2H), 6.78 (d,
J=8.7 Hz, 2H), 5.02 (s, 1H), 4.94 (s, 2H), 4.88 (s, 2H), 3.69 ppm (s,
3H); 13C NMR (101 MHz, CDCl3): d=199.4, 159.4, 158.0, 156.0,
136.9, 130.6, 130.1, 129.1, 128.7, 128.6, 128.5, 128.2, 127.9, 127.4,
126.6, 121.0, 115.0, 113.9, 112.1, 70.0, 70.0, 58.0, 55.2 ppm.
1-(2-Fluorophenyl)-8-oxatricyclo[7.4.0.02,7]trideca-2(7),3,5-trien-5-
ol (8g): Following general procedure H, the title compound was
isolated as a colorless oil after silica gel chromatography in 15%
1
yield (5 g) over two steps: H NMR (400 MHz, CDCl3): d=7.24–7.17
(m, 1H), 7.04 (ddd, J=12.4, 8.1, 1.3 Hz, 1H), 6.98 (dd, J=7.8, 1.3 Hz,
1H), 6.96 (d, J=8.0 Hz, 1H), 6.89 (td, J=8.1, 1.8 Hz, 1H), 6.44 (dd,
J=8.0, 2.3 Hz, 1H), 6.40 (d, J=2.2 Hz, 1H), 5.13 (ddd, J=7.0, 5.5,
1.9 Hz, 1H), 2.40–2.29 (m, 1H), 2.07–1.98 (m, 2H), 1.74–1.57 (m,
3H), 1.57–1.45 (m, 1H), 1.43–1.30 ppm (m, 1H); 13C NMR (101 MHz,
CDCl3): d=161.0 (d, J=247.0 Hz), 160.5, 156.5, 133.7 (d, J=
10.0 Hz), 128.9 (d, J=4.4 Hz), 128.5 (d, J=8.9 Hz), 124.9, 124.8,
123.8 (d, J=3.4 Hz), 116.5 (d, J=23.2 Hz), 107.3, 98.8 (s), 88.3 (d,
J=5.0 Hz), 50.5 (d, J=3.2 Hz), 31.9 (d, J=3.6 Hz), 28.0, 21.2,
19.6 ppm; HRMS-ESI: m/z [M+H]+ calcd for C19H20FO2: 285.1291,
found: 285.1281.
9b-(4-(Benzyloxy)phenyl)-1,4,4a,9b-tetrahydrodibenzo[b,d]furan-
3(2H)-one (15): A solution of KOH in EtOH (7.6 mL, 3m) was added
to a mixture of 14 (100 mg, 023 mmol) and methyl vinyl ketone
(0.021 mL, 0.25 mmol) in THF (3 mL) at 08C. The reaction was al-
lowed to reach room temperature and was stirred overnight. The
mixture was neutralized with HCl (2m) and diluted with Et2O
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CHEMMEDCHEM
FULL PAPERS
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(10 mL), and the organic layer was extracted, dried over Na2SO4,
and concentrated. The reaction mixture was re-dissolved in EtOH
(10 mL), and conc. HCl (1 mL) was added. The mixture was heated
to reflux for 3 h, then diluted with Et2O (10 mL) and washed with
NaHCO3 and brine, dried over Na2SO4, and concentrated. The crude
product was purified by silica gel chromatography (gradient: 10:1–
5:1–1:1, pentane/EtOAc) to yield the title compound as a clear oil
1
in 32% yield (27 mg): H NMR (400 MHz, CDCl3): d=7.46–7.33 (m,
6H), 7.30 (d, J=8.8 Hz, 2H), 7.20 (t, J=7.6 Hz, 1H), 6.97 (d, J=
8.1 Hz, 2H), 6.92 (t, J=7.3 Hz, 1H), 6.84 (d, J=8.1 Hz, 1H), 5.13 (t,
J=3.1 Hz, 1H), 5.07 (s, 2H), 2.85 (ddd, J=40.0, 17.0, 3.2 Hz, 2H),
2.73 (td, J=14.0, 3.3 Hz, 1H), 2.41 (dt, J=18.3, 3.3 Hz, 1H), 2.27 (dt,
J=13.8, 3.7 Hz, 1H), 2.02 ppm (ddd, J=18.4, 14.2, 4.2 Hz, 1H).
9b-(4-Hydroxyphenyl)-1,4,4a,9b-tetrahydrodibenzo[b,d]furan-
3(2H)-one (16): Following general procedure H, the title com-
pound was isolated after silica gel chromatography in 60% yield
1
(5 mg): H NMR (400 MHz, CDCl3): d=7.27–7.23 (m, 3H), 7.19 (ddd,
J=8.1, 7.1, 1.7 Hz, 1H), 6.98–6.89 (m, 2H), 6.82 (d, J=8.9 Hz, 2H),
5.12 (t, J=3.2 Hz, 1H), 4.93 (s, 1H), 2.85 (ddd, J=40.6, 17.0, 3.3 Hz,
2H), 2.71 (td, J=14.1, 3.5 Hz, 1H), 2.41 (dt, J=18.4, 3.4 Hz, 1H),
2.26 (dt, J=13.9, 3.8 Hz, 1H), 2.01 ppm (ddd, J=18.4, 14.2, 3.9 Hz,
1H); 13C NMR (101 MHz, CDCl3): d=209.2, 159.5, 154.5, 138.1,
132.8, 129.1, 128.0, 124.9, 121.5, 115.5, 109.7, 89.3, 51.8, 41.8, 35.9,
31.6 ppm; HRMS-ESI: m/z [M+H]+ calcd for C18H17O3: 281.1178,
found: 281.1188.
[7] a) F. Piu, C. Cheevers, L. Hyldtoft, L. R. Gardell, A. L. Del Tredici, C. B. An-
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9b-(4-(Benzyloxy)phenyl)-3,3-difluoro-1,2,3,4,4a,9b-
hexahydrodibenzo[b,d]furan (17): DAST (0.129 g, 0.29 mmol, 50%
wild-type in CH2Cl2) was added to a stirred solution of 16 (0.027 g,
0.037 mmol) in CH2Cl2 (1 mL). The mixture was stirred overnight
and filtered to give a mixture of gem-difluoro species with traces
of vinyl fluoride in a crude yield of 52%. The reaction was used
without further purification in the next step.
4-(7,7-Difluoro-5a,6,7,8,9,9a-hexahydrodibenzo[b,d]furan-9a-yl)-
phenol
(gem-difluoro)
(18)
and
4-(7-fluoro-5a,6,9,9a-
tetrahydrodibenzo[b,d]furan-9a-yl)phenol (vinyl fluoride): Fol-
lowing general procedure H, the gem-difluoro was isolated after
silica gel chromatography in 26% yield (3 g): 1H NMR (400 MHz,
CDCl3): d=7.20–7.14 (m, 1H), 7.07 (d, J=8.8 Hz, 2H), 6.97 (dd, J=
7.4, 1.5 Hz, 1H), 6.90 (td, J=7.4, 0.9 Hz, 1H), 6.85 (d, J=8.0 Hz, 1H),
6.73 (d, J=8.8 Hz, 2H), 5.02–4.96 (m, 1H), 4.69 (s, 1H), 2.44–2.24
(m, 3H), 2.22–2.12 (m, 1H), 2.11–1.95 (m, 1H), 1.92–1.74 ppm (m,
1H); 13C NMR (101 MHz, CDCl3): d=158.5, 154.4, 136.5, 133.7,
129.0, 128.2, 124.1, 122.65 (d, J=242.8 Hz), 121.4, 115.4, 110.8, 87.9
(dd, J=6.6, 4.3 Hz), 51.4 (s), 35.6 (d, J=25.5 Hz), 30.6 (t, J=
24.2 Hz), 30.2 ppm (dd, J=6.4, 3.6 Hz).
[15] O. Mitsunobu, Synthesis 1981, 1–28.
[16] Compound 8g represents the benzofuranol scaffold; additional ana-
logues of 8 were synthesized (data not included).
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2006, 12, 1717–1729; e) B. W. Lund, F. Piu, N. K. Gauthier, A. Eeg, E. Cur-
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Abbreviations: estrogen receptor a (ERa), estrogen receptor b
(ERb), 17b-estradiol (E2), diethylaminosulfur trifluoride (DAST), 4-di-
methylaminopyridine, (DMAP), diethyl azodicarboxylate (DEAD), dii-
sopropyl azodicarboxylate (DIAD), Dess–Martin periodinane (DMP),
structure–activity relationship (SAR), tetrabutylammonium fluoride
(TBAF).
Acknowledgements
We gratefully acknowledge the Michael J. Fox foundation for
funding.
Keywords: asymmetric synthesis
· neurological agents ·
estrogen receptors · modulators · Parkinson’s disease
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N. K. Gauthier, M. Begtrup, U. Hacksell, R. Olsson, J. Med. Chem. 2009,
52, 1540–1545; i) G. Gaubert, F. Bertozzi, N. M. Kelly, J. Pawlas, A. L.
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Chem. 2006, 49, 4805–4808.
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10, 778–792.
Received: April 19, 2013
[20] Schrçdinger Suite 2012, Schrçdinger LLC, New York, NY, 2012.
Published online on && &&, 0000
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