Synthesis of 3-alkyl naphthalenes as novel estrogen receptor ligands

Article abstract of DOI:10.1016/j.bmcl.2008.07.121

A series of estrogen receptor ligands based on a 3-alkyl naphthalene scaffold was synthesized using an intramolecular enolate-alkyne cycloaromatization as the key step. Several of these compounds bearing a C6-OH group were shown to be high affinity ligand

Full text of DOI:10.1016/j.bmcl.2008.07.121

Bioorganic & Medicinal Chemistry Letters 18 (2008) 5075–5077
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Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis of 3-alkyl naphthalenes as novel estrogen receptor ligands
*
Jing Fang , Adwoa Akwabi-Ameyaw, Jonathan E. Britton, Subba R. Katamreddy, Frank Navas III,
Aaron B. Miller, Shawn P. Williams, David W. Gray, Lisa A. Orband-Miller, Jean Shearin, Dennis Heyer
GlaxoSmithKline Research, 5 Moore Drive, Research Triangle Park, NC 27709, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of estrogen receptor ligands based on a 3-alkyl naphthalene scaffold was synthesized using an
intramolecular enolate-alkyne cycloaromatization as the key step. Several of these compounds bearing
Received 20 June 2008
Revised 29 July 2008
Accepted 31 July 2008
Available online 5 August 2008
a C6-OH group were shown to be high affinity ligands. All compounds had similar ER
affinity ranging from micromolar to low nanomolar.
a and ERb binding
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
Estrogen receptor ligands
ER binding
Naphthalene
Estrogen receptors (ER) are members of the superfamily of li-
gand-modulated nuclear receptors that mediate the actions of ste-
roid hormones, vitamin D, retinoids, and thyroid hormones.1
Naturally occurring estrogens such as 17b-estradiol have been
used in hormone replacement therapy (HRT) by postmenopausal
women for the treatment of osteoporosis and hot flush. Although
HRT is effective, it has been associated with increased risk of car-
diovascular disease and breast cancer.2 Selective estrogen receptor
modulators (SERMs) are a class of therapeutic agents that provide
the benefit of estrogen while limiting some associated liabilities.
Their tissue selectivity allows them to function as estrogen ago-
nists in certain tissues, while acting as estrogen antagonists in
other tissues. The clinical utility of SERMs has been exemplified
with tamoxifen3 for the prevention and treatment of breast cancer
and raloxifene4 for the prevention of osteoporosis and breast can-
cer in postmenopausal women.5
A series of estrogen receptor ligands derived from a naphtha-
lene scaffold was previously reported by researchers at Eli Lilly.6
However, the reported scope of this series was limited by a lack
of substitution at the C3 position of the naphthalene skeleton
(R3 = H, Fig. 1).
Our interest in exploring substitution at the C3 position was
motivated by an X-ray crystal structure of one of our naphthalene
analogues GW2368 bound to ERa, which revealed an unfilled
O
HO
O
R2
R3
R1
C3 position
Figure 1. Generic structure of naphthalene SERMs.
report the synthesis of a series of C3-substituted naphthalenes
and their binding affinity against ERa and ERb.
We have previously explored several routes to prepare func-
tionalized naphthalene-based ER ligands.7 These earlier efforts in-
cluded a squarate-based ring expansion chemistry approach as
well as an attempt to adopt the route originally developed by
researchers at Lilly. Unfortunately, while both of these approaches
afforded some of our target compounds, they proved to be long, te-
dious, and subject to highly variable yields. Accordingly, rapid
development of SAR at the C3 position demanded a more efficient
synthetic route.
We focused our attention on two reports in the literature,8,9
describing an intramolecular cycloaromatization strategy to con-
struct 3-alkyl-1-naphthols. We envisioned that a substrate like 1
would probably undergo a similar benzannulation reaction to yield
3-alkyl-2-aryl-1-naphthol core, which could be used as a suitable
intermediate for the generation of new ER ligands.
hydrophobic region of the ligand binding pocket adjacent to the
C3 position (shown in yellow in Fig. 2). We hypothesized that
incorporation of lipophilic substituents at the C3 position might
provide analogues with increased ER binding affinity. We herein
Phenylethanone 1 was prepared by three-step process (Scheme
1). Sonogashira coupling of methyl 2-iodobenzoate with 1-hexyne
* Corresponding author. Tel.: +1 919 483 8698; fax: +1 919 315 0430.
E-mail address: jing.m.fang@gsk.com (J. Fang).
0960-894X/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2008.07.121

5076
J. Fang et al. / Bioorg. Med. Chem. Lett. 18 (2008) 5075–5077
HO
HO
OH
O
GW 2368
Figure 2. X-ray structure of GW2368 bound to ER
a
(RCSB Protein Data Bank ID: 3DT3).
O
O
O
O
I
O
N
OMe
ii
iii
i
OMe
Bu
Bu
Bu
3
1
2
Scheme 1. Reagents and conditions: (i) 1-hexyne, Pd(PPh3)2Cl2, CuI, DIPEA, DMF; (ii) N,O-dimethylhydroxylamine HCl salt, nBuLi, À20 °C; (iii) benzylmagnesium chloride,
THF, 0 °C.
provided o-hexynylbenzoate 2,10 which was then reacted with the
lithium salt of N,O-dimethylhydroxylamine to give Weinreb amide
3.11 Treatment of 3 with benzylmagnesium chloride in THF affor-
ded 1 in 78% yield.12
A variety of cycloaromatization conditions were applied to phe-
nylethanone 1. Deprotonation of this ketone with KHMDS (1.2
equiv) in toluene at À78 °C followed by heating at 80 °C for an hour
gave the desired naphthol 4 in 68% yield (Scheme 2).13
Similar to what was reported previously,9 a potassium counter-
ion appears to be required. KOtBu and KH in THF provided 4 in
comparable yields, but NaOMe, NaH and NaOtBu in THF afforded
either none or a very low yield of the desired product along with
O
OH
1) KHMDS (1.2 eq.), PhMe
2) aqueous, HCl
Bu
4
1
Scheme 2.
R2
iii
R2
O
O
O
OH
OMe
ii
i
OMe
R1
R1
R1
(Br, OTf)
R1
R3
R3
R3
5
7
8
6
O
O
O
H
HO
HO
R2
R2
R2
O
O
O
iv
v
vi
R1 = OMe
or
R2 = OMe
R1
R3
R1
R3
HO
R3
C6 position
C6 position
10 a-e
9
11 a-e
Scheme 3. Reagents and conditions: (i) HC„C-R3, Pd(PPh3)2Cl2, CuI, DIPEA, DMF; (ii) a—N,O-dimethylhydroxylamine HCl salt, nBuLi, À20 °C; b—ArCH2MgCl, THF, 0 °C; (iii)
KHMDS, toluene, 80 °C; (iv) 4-F benzaldehyde, base, heat; (v) a—nBuLi, (EtO)2POCH2CO2Et; b—NaOH, heat; or malonic acid, piperidine, Py., heat; (vi) BBr3, CH2Cl2.

J. Fang et al. / Bioorg. Med. Chem. Lett. 18 (2008) 5075–5077
5077
Table 1
ER and ERb binding data
accommodating unbranched alkyl chains in this region of the bind-
ing pocket resulting in a loss of binding affinity.
In summary, we have modified a previously described cycloaro-
matization procedure to prepare a series of 3-alkyl substituted
a
Compound
R1
R2
R3
ER
(nM)
a
binding Ki
ERb binding Ki
(nM)
naphthalenes with good affinity for ER
a and ERb. This route pro-
Estradiol
Raloxifene
10a
10b
10c
10d
10e
11a
11b
—
—
H
H
H
H
H
OH
OH
OH
OH
OH
—
—
H
H
—
—
2
2
2
23
vides a more efficient approach to the naphthalene scaffold than
those previously reported for structurally related ER ligands, and
provides a method to directly examine the impact of substitution
at the C3-position on binding to estrogen receptors.
CH3OCH2
Bu
Bu
Bu
Bu
cyclo-Pr
Bu
i-Bu
Pentyl
Octyl
692
977
724
158
52
60
4
28
2
55
501
170
110
162
48
16
4
22
3
F
OCH3
OH
H
H
H
References and notes
11c
11d
11e
1. Karnik, P. S.; Kulkarni, S.; Liu, X. P.; Budd, G. T.; Bukowski, R. M. Cancer Res.
1994, 54, 349.
2. Writing Group for the Women’s Health Initiative Investigators. J. Am. Med.
Assoc. 2002, 288, 321.
H
H
30
3. Jordan, V. C. Breast Cancer Res. Treat. 1988, 11, 197.
4. Delmas, P. D. et al J. Clin. Endocrinol. Metab. 2002, 87, 3609.
5. Vogel, V. G.; Costantino, J. P.; Wickerham, D. L., et al J. Am. Med. Assoc. 2006, 295,
2727.
6. Hauser, K. L.; Palkowitz, A. D., et al. European Patent 0835867A1, 1998.
7. Heyer, D.; Fang, J.; Navas, F., III; Katamreddy, S. R.; Peckham, J. P.; Turnbull, P.
S.; Miller, A. B.; Akwabi-Ameyaw, A. PCT Int. Application WO2006002185A1,
2006.
8. Ciufolini, M. A.; Weiss, T. J. Tetrahedron Lett. 1994, 35, 1127.
9. Makra, F.; Rohloff, J. C.; Muehldorf, A. V.; Link, J. O. Tetrahedron Lett. 1995, 36,
6815.
10. Shi, C.; Zhang, Q.; Wang, K. K. J. Org. Chem. 1999, 64, 925.
11. Raap, J.; Nieuwenhuis, S.; Creemers, A.; Hexspoor, S.; Kragl, U.; Lugtenburg, J.
Eur. J. Org. Chem. 1999, 2609.
12. Hu, Y.; Baudart, S.; Porco, J. A., Jr. J. Org. Chem. 1999, 64, 1049.
13. General procedure for cycloaromatization: A solution of acetophenone 1 (0.88 g,
3.18 mmol) in toluene (8 mL) was added to a solution of KHMDS in toluene
(0.5 M, 1.2 equiv) at À78 °C under N2. After completion of addition, the cold
bath was removed, and the reaction mixture was allowed to warm up to room
temperature, then heated at 80 °C for 1 h. The reaction mixture was then
cooled in an ice bath, quenched with 2 N HCl, diluted with 50 mL of water, and
extracted with EtOAc. The organic extracts were combined and washed with
brine, dried over Na2SO4, filtered, and evaporated in vacuo. The residue was
chromatographed on silica gel (5% EtOAc in hexanes) to afford naphthol 4 as a
light yellow solid (0.60 g, 68%). 1H NMR (400 MHz, CDCl3): d 0.76 (t, J = 7.3 Hz,
3H), 1.15–1.30 (m, 2H), 1.45–1.55 (m, 2H), 2.49 (t, J = 7.8 Hz, 2H), 5.20 (s, 1H),
7.33 (s, 1H), 7.36 (d, J = 7.0 Hz, 2H), 7.39–7.50 (m, 3H), 7.50–7.57 (m, 2H), 7.75
(d, J = 7.9 Hz, 1H), 8.18 (d, J = 8.0 Hz, 1H).
14. Zhang, Q.; Shi, C.; Zhang, H. R.; Wang, K. K. J. Org. Chem. 2000, 65, 7977.
15. Dimmock, J. R.; Puthucode, R. N.; Smith, J. M.; Hetherington, M.; Quail, J. W.;
Pugazhenthi, U.; Lechler, T.; Stables, J. P. J. Med. Chem. 1996, 39, 3984.
16. Martyn, D. C.; Hoult, D. A.; Abell, A. D. Aust. J. Chem. 2001, 54, 391.
17. Wu, G.; Schumacher, D. P.; Tormos, W.; Clark, J. E.; Murphy, B. L. J. Org. Chem.
1997, 62, 2996.
multiple by-products. Refluxing 1 with 1 equiv of camphorsulfonic
acid in CHCl3 only resulted in a trace amount of 4.
Using this cycloaromatization reaction, we synthesized various
3-alkyl-2-aryl-1-naphthols 8 starting from an appropriate aryl
bromide or aryl triflate 5 for the Sonogashira coupling14 (Scheme 3).
1-Naphthol 8 was then heated with 4-F benzaldehyde in the pres-
ence of a base (NaH or Cs2CO3)15 to give aryloxy benzaldehyde 9.
Formyl group of 9 was converted to acrylic acid side chain of
10a–e using Horner-Emmons olefination16 followed by saponifica-
tion or Knoevenagel condensation17with malonic acid in pyridine.
When R1 = OMe, demethylation with BBr3 in CH2Cl2 yielded C6-OH
naphthalene analogues 11a–e.
Compounds 10a–e and 11a–e were tested for their ability to
compete with 3H-estradiol for binding to full length biotinylated
human ER
with the observed binding mode of GW2368 to ER
a
and ERb linked to an SPA bead (Table 1).7 Consistent
a
, the C6-H
(des hydroxyl) analogues 10a–e are significantly less potent than
the corresponding C6-OH analogues 11a–e due to the inability of
10a–e to form hydrogen bonds with Glu 353 and Arg 394 in ER
a
and Glu 305 and Arg 346 in ERb.18 Enhanced potency in the
R1 = H series was observed with the R2 phenol analogue 10e, which
is well positioned to form a hydrogen bond with His-524 (ERa) or
His-475 (ERb).18 In general, small unbranched alkyl groups are well
tolerated at C3 position of the naphthalenes as predicted in Figure
2. The octyl analogue (11e) appears to approach the steric limit for
18. Jordan, V. C. J. Med. Chem. 2003, 46, 883.