An ortho-quinodimethane route to Lasofoxifene and U23469

Article abstract of DOI:10.1246/cl.2011.1272

Lasofoxifene, a third-generation selective estrogen receptor modulator, could be synthesized via regio-and stereoselective [4 + 2] cycloaddition between an ortho-quinodimethane and a borylalkene. This protocol was also applicable to the synthesis of antie

Full text of DOI:10.1246/cl.2011.1272

doi:10.1246/cl.2011.1272
1272
Published on the web October 22, 2011
An ortho-Quinodimethane Route to Lasofoxifene and U23469
Hiroto Yoshida,* Ryuma Yoshida, Masashi Mukae, Joji Ohshita, and Ken Takaki
Department of Applied Chemistry, Graduate School of Engineering, Hiroshima University,
Higashi-Hiroshima, Hiroshima 739-8527
(Received August 9, 2011; CL-110667; E-mail: yhiroto@hiroshima-u.ac.jp)
Lasofoxifene, a third-generation selective estrogen receptor
report on a unique route to 1, whose core skeleton is assembled
regio- and stereoselectively through cycloaddition using an
o-QDM. Furthermore, a cis-1,2-diaryltetralin with antiestrogenic
effect, U23469,10 can also be synthesized depending upon this
protocol.
modulator, could be synthesized via regio- and stereoselective
[4 + 2] cycloaddition between an ortho-quinodimethane and a
borylalkene. This protocol was also applicable to the synthesis
of antiestrogen U23469.
First we prepared the required o-QDM precursor 2 possess-
ing a benzylsilyl and a benzhydryl benzoate moieties from
commercially available 2-bromo-5-methoxytoluene in five steps
as described in Scheme 2.11,12 Subsequent cycloaddition of the
o-QDM, generated in situ from 2 and a fluoride ion (KF/18-
crown-6),13 with (E)-¢-borylstyrene in THF at 35 °C resulted in
the preferential formation of boryltetralin 3 (3:3¤:3¤¤ = 82:10:8,
56% yield), where two aryl groups are adjoining in cis
configuration (Scheme 3). The observed regio- and stereo-
selectivities can be rationally explained by the following two
factors: exo approach of the bulky B(pin) moiety which orients
the ¡-aryl group of the o-QDM to a remote position, and a
secondary orbital interaction between C-2 of the o-QDM and the
phenyl group of (E)-¢-borylstyrene. Oxidation of the C-B bond
of boryltetralins provided alcohols 4-4¤¤ in 80% yield, from
which the requisite isomer was isolated by reversed-phase
HPLC. The obtained alcohol 4 was then transformed into
xanthate 5 by reaction with carbon disulfide and methyl iodide.
Deoxygenation of 5 via the Barton-McCombie reaction14 using
tributyltin hydride gave a 96% yield of 6,15 whose methoxy-
methyl moiety was deprotected by treatment with TMSBr. The
hydroxy group of 7 was alkylated with 1-(2-chloroethyl)pyrro-
Much attention has been riveted on synthetic utilization of
o-quinodimethanes (o-QDMs) as an efficient four-carbon unit in
constructing 6-membered carbocyclic frameworks via [4 + 2]
cycloaddition (Diels-Alder reaction).1 Although the cycloaddi-
tion enables diverse tetralin derivatives of synthetic significance
such as steroids,2 alkaloids,3 polyacenes,4 and fullerenes5 to be
synthesized in a straightforward manner, potential versatility of
the reaction remains to be exploited.6 In this regard, we have
recently disclosed that the cycloaddition between o-QDMs and
borylalkenes offered facile access to boryltetralins of structural
diversity, which were further convertible into variously sub-
stituted borylnaphthalenes via oxidative aromatization.7 More-
over, the cycloaddition of ¡-arylated o-QDMs with (E)-¢-
borylstyrene was found to proceed with a high level of regio-
and stereoselectivities, affording high yields of cis-1,2-diaryl-
tetralins in a straightforward manner (eq 1).
B(pin)
B(pin)
[4+2]
ð1Þ
+
O
O
o-QDM
MeO
Me
Br
MeO
B(pin):
B
NBS, AIBN
Br
CCl4, reflux, 18 h
78%
Br
Lasofoxifene (1) is a potent third-generation selective
estrogen receptor modulator (SERM), which reduces risks of
fractures, ER-positive breast cancer and coronary heart disease
in postmenopausal women with osteoporosis.8 As shown in
Scheme 1, the structural feature of 1 is the presence of cis-1,2-
diaryltetralin motif, and all of the reported syntheses of 1 thus
far utilize hydrogenation of 1,2-dihydronaphthalene derivatives
for making the motif, to the best of our knowledge.9 Herein we
MeO
MeO
Mg, TMSCl
NBS
TMS
TMS
THF, rt, 18 h
69%
CCl4, 0 °C, 71 h,
then rt, 70 h
quant
TMS
Br
MeO
TMS
OH
4-MOMOC6H4CHO
n-BuLi
THF, -78 °C, 3.5 h -78 °C to rt, 16 h
HO
75%
RO
OMOM
hydrogenation
MeO
TMS
OBz
Bz2O, pyridine, DMAP
O
N
OR'
CH2Cl2, rt, 22 h
55%
Lasofoxifene (1)
2
OMOM
Scheme 1. Synthesis of lasofoxifene via hydrogenation of a
1,2-dihydronaphthalene derivative.
Scheme 2. Synthesis of o-QDM precursor 2.
Chem. Lett. 2011, 40, 1272-1274
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MeO
MeO
MeO
B(pin)
Ph
MeO
OH
Cl
OH
Ph
K2CO3
7
MeCN, reflux, 22 h
70%
OH
OMOM
O
OH
3
U23469
+
B(pin)
Ph
Scheme 4. Synthesis of U23469.
(E )-PhC=CB(pin)
KF, 18-crown-6
2
MeO
Ph
THF, 35 °C, 72 h
56%, 3:3':3" = 82:10:8
Ph
KF, 18-crown-6
+
2
6
OMOM
3'
THF, 35 °C, 24 h
47%, 6:6' = 54:46
+
Ph
OMOM
6'
B(pin)
Scheme 5. [4 + 2] Cycloaddition using styrene.
diaryltetralin with biological activity. Thus, alkylation of 7 by
use of 3-chloro-1,2-propanediol gave antiestrogen, U23469 in
70% yield (Scheme 4).
Although [4 + 2] cycloaddition between the o-QDM and
styrene was a promising shortcut to 1, this reaction gave a
mixture of 6 and its stereoisomer 6¤ in almost the same ratio,
demonstrating the indispensable role of the boryl group in
achieving high stereoselectivity (Scheme 5).
OMOM
3"
MeO
OH
Ph
H2O2, NaOH
+ 4' + 4"
THF, 50 °C, 3.5 h
80%
4: 58% after separation
OMOM
4
In conclusion, the [4 + 2] cycloaddition between an o-QDM
and a borylalkene has been demonstrated to be a potent protocol
for regio- and stereoselective construction of a cis-1,2-diaryl-
tetralin motif, allowing lasofoxifene and U23469 to be synthe-
sized from 2-bromotoluene, arylaldehyde, and borylalkene.16
The high availability of these components makes the present
method advantageous in diversifying lasofoxifene framework.
Efforts are currently directed toward synthesis of pharmacolog-
ically significant molecules of other types having cis-1,2-
diaryltetralin motifs by use of the present protocol.
MeO
O
SMe
1. NaH, imidazole, 3.5 h
2. CS2,1 h
S
Ph
3. MeI, 40 min
THF, reflux
97%
OMOM
5
MeO
Bu3SnH
AIBN
Ph
TMSBr
References and Notes
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© 2011 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/

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Chem. Lett. 2011, 40, 1272-1274
© 2011 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/