An expeditious synthesis of lasofoxifene and nafoxidine via the novel three-component coupling reaction

Article abstract of DOI:10.1246/cl.2007.40

The simple and efficient synthesis of lasofoxifene (4), a possible candidate for alleviating osteoporosis, via the novel three-component coupling reaction among 4-pivaloyloxybenzaldehyde (5), cinnamyltrimethylsilane (6), and anisole in the presence of HfCl₄ is illustrated. The successive cationic cyclization of the coupling product, olefin formation, and migration of the double-bond are performed to afford the common synthetic intermediate of lasofoxifene (4) and nafoxidine (3) via a very concise procedure. Copyright

Full text of DOI:10.1246/cl.2007.40

40
Chemistry Letters Vol.36, No.1 (2007)
An Expeditious Synthesis of Lasofoxifene and Nafoxidine
via the Novel Three-component Coupling Reaction
Yoshiyuki Sano, Kenya Nakata, Takafumi Otoyama, Sei Umeda, and Isamu ShiinaÃ
Department of Applied Chemistry, Faculty of Science, Tokyo University of Science,
Kagurazaka, Shinjuku-ku, Tokyo 162-8601
(Received October 2, 2006; CL-061151; E-mail: shiina@rs.kagu.tus.ac.jp)
The simple and efficient synthesis of lasofoxifene (4), a
tion of 3 will be equivalent to the completion of the formal total
synthesis of 4. According to this synthetic plan, we started to
develop a novel method for the preparation of 3 and 4 through
the three-component coupling reaction as part of our continuous
efforts to apply this novel synthetic methodology to afford new
types of SERMs.
We first investigated the three-component coupling reaction
among 4-pivaloyloxybenzaldehyde (5), cinnamyltrimethylsilane
(6), and anisole under several reaction conditions to optimize the
suitable ratio of catalysts to substrates based on the former re-
sults reported for the synthesis of tamoxifen (1) and droloxifene
(2).2 These results are summarized in Table 1.
possible candidate for alleviating osteoporosis, via the novel
three-component coupling reaction among 4-pivaloyloxybenzal-
dehyde (5), cinnamyltrimethylsilane (6), and anisole in the pres-
ence of HfCl4 is illustrated. The successive cationic cyclization
of the coupling product, olefin formation, and migration of
the double-bond are performed to afford the common synthetic
intermediate of lasofoxifene (4) and nafoxidine (3) via a very
concise procedure.
We have recently established a novel three-component cou-
pling reaction among aromatic aldehydes, allylsilanes, and aro-
matic nucleophiles in the presence of a Lewis acid catalyst.1 This
sequential one-pot allylation and the Friedel–Crafts type alkyla-
tion affords 3,4,4-trisubstituted butene (A) via the intermediate
homoallyl silyl ether. Furthermore, it has been demonstrated that
the coupling reaction could be effectively used for the prepara-
tion of SERMs (selective estrogen receptor modulators), such
as tamoxifen (1), idoxifene, and droloxifene (2) (Scheme 1).2
It is assumed that the structure of the 3,4,4-triarylbutene
intermediate A generated from the three-component coupling
reaction would also be a suitable molecule as a precursor of
lasofoxifene (4), a hopeful candidate for the treatment of osteo-
porosis,3 and nafoxidine (3);4 that is, the terminal olefin part in A
could react with one of the two aromatic rings at the 4-position
by an appropriate electrophilic cyclization to produce a dihydro-
naphthalene structure B. The successive base-induced double-
bond migration of B and installing the side-chain onto C might
produce 3. Since it is already known that 3 could be easily con-
verted to 4 by hydrogenation of the double-bond as shown in the
above instances,3 establishment of the method for the prepara-
The three-component coupling reaction smoothly proceeded
at room temperature in the presence of HfCl4 without the co-
catalyst to give the coupling product 7 in high yield using a
two-fold amount of 6 to 5 (Entries 4–6). On the other hand,
the combined use of HfCl4 and TMSOTf as a co-catalyst, pref-
erentially increased the yields of triarylmethanes 8, which were
produced from a 1 molar amount of 5 and 2 molar amounts of
anisole (Entries 1–3); therefore, aldehyde 5 was apparently
over-activated by the addition of the co-catalyst. As shown in
Entry 6, the coupling reaction with high concentrations of the
reactants decreased the yield of the desired compound because
the concentration of anisole simultaneously decreased in the
reaction conditions.
All the coupling reactions listed in Table 1 afforded a ca. 2:3
mixture of the syn and anti diastereomers of the 3,4,4-trisubsti-
tuted butenes 7. The ratio of the diastereomers was determined
by 1H NMR and HPLC analyses. Because these compounds
could not be separated at this stage, a diastereomeric mixture
of the coupling products was used for the next carbocyclization
Table 1. The three-component coupling reaction among 4-
pivaloyloxybenzaldehyde (5), cinnamyltrimethylsilane (6), and
anisole using HfCl4/TMSOTf as the catalyst
OMe
OR3
OR3
O
Lewis acid
H
+
+
SiMe3
R1
Three-component
coupling reaction
O
R1
R2
OMe
catalyst, rt
OMe
R2
H
A
+
+
SiMe3
N
O
PivO
OMe
OR3
PivO
PivO
5
6
R1 = R2 = H ;
Tamoxifen (1)
(solvent)
7
8
Double-bond
migration
Side-chain
installation
A
Molar
ratio
of 5/6
Yield
of 7
/%
R1 = H, R2 = OH;
Droloxifene (2)
R1
R1
Catalyst/equiv.
Time Conc.
/h
R2
R2
Entry
1
Electrophilic
cyclization
/M
HfCl4 TMSOTf
N
N
OR3
OR3
O
O
complex
mixture
34
43
63
1.0
0.50
1/1.2
20
0.1
Double-bond
migration
Side-chain
installation
Hydrogenation
2
3
4
5
6
1.0
1.0
1.0
1.0
1.0
0.25
1/1.2
1/1.2
1/2
1/2
1/2
20
20
20
2
0.1
0.1
0.1
0.3
0.8
R1
R1
R1
R1
0
0
0
0
R1 = OMe; Nafoxidine (3) R1 = OH; Lasofoxifene (4)
B
C
78
54
Scheme 1. Newly developed synthetic pathway of tamoxifen
derivatives via the novel three-component coupling reaction.
20
Copyright Ó 2007 The Chemical Society of Japan

Chemistry Letters Vol.36, No.1 (2007)
41
NOE
OPiv
OMe
N
OMe
OH
O
H
H
I(py)2BF4
N
•
Cl
BF3 OEt2
t-BuOK (4 equiv.)
degassed DMSO
+
NaH
H
CH2Cl2
-78 oC, 2 h
9
DMF, 50 o
82%
C
MeO
I
PivO
PivO
I
90 oC
89%
68%
H
7
9
10
MeO
MeO
41%
27%
12
NOE
Nafoxidine (3)
Scheme 2. Iodine-induced cationic carbocyclization.
N
N
O
O
H2 (2.5 atm)
Pd(OH)2/C
OPiv
OH
BBr3
EtOH, 50 oC
70%
DBU
t-BuOK (6.5 equiv.)
CH2Cl2
9
-23 to 0 oC
76%
Toluene, 95 oC
75%
DMSO, rt
70%
MeO
HO
13
Lasofoxifene (4)
MeO
MeO
11
12
Scheme 4. Synthesis of lasofoxifene (4) and nafoxidine (3) via
direct conversion of iodide intermediate 9 into the common
precursor 12.
Scheme 3. Formation of dihydronaphthalene derivatives.
step. It was anticipated that both compounds might be converted
into the corresponding dihydronaphthalene derivatives by the
double-bond migration in the later step.
Some electrophilic cyclization reactions were then carried
out to transform 7 into the corresponding dihydronaphthalenes.
in 13 by BBr3 (Scheme 4).
Thus, we developed a novel method to produce lasofoxifene
(4) and nafoxidine (3) using the three-component coupling
reaction among 4-pivaloyloxybenzaldehyde (5), cinnamyltri-
methylsilane (6), and anisole in the presence of HfCl4. The inter-
mediary 3,4,4-triarylbutene derivative 7 was effectively trans-
formed into 3 as a precursor of 4 via the successive three-step
transformations; namely, cationic cyclization, sequential dou-
ble-bond formation/migration, and side-chain installation.
.
First, no desirable cyclization occurred when the NBS/BF3
OEt2-mediated reaction was applied to the electrophilic cycliza-
tion of 7. Therefore, we tried the iodine-induced cationic
cyclization of 7 using bis(pyridine)iodonium tetrafluoroborate
(I(py)2BF4), which was developed by Barluenga et al.5 Fortu-
nately, the desired cyclization smoothly took place in the
.
This study was partially supported by a Research Grant
from the Center for Green Photo-Science and Technology,
and Grants-in-Aid for Scientific Research from the Ministry of
Education, Culture, Sports, Science and Technology, Japan.
presence of stoichiometric amounts of I(py)2BF4/BF3 OEt2,
and two carbocyclized products 9 and 10 were predominantly
obtained in good yields as shown in Scheme 2. It is noteworthy
that the cyclized compounds 9 and 10 have all trans configura-
tions and the reaction exclusively afforded these positional iso-
mers 9 and 10 in 41 and 27% yields, respectively. The ratio of
yields of 9 to 10 might correspond to the diastereomeric ratio
of the triarylbutene 7 generated by the coupling reaction. The
stereochemistry of both cyclized compounds was determined
by the coupling constants of the 1H NMR spectroscopy, and
the positions of the methoxy and pivaloyloxy groups in 9 and
10 have been deduced by the observation of enhanced NOEs
of these compounds as depicted in Scheme 2.
The authors dedicate this paper to Professor Teruaki
Mukaiyama on the celebration of his 80th birthday.
References and Notes
1
2
3
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Simmons, D. D. Thompson, Endocrinology 2000, 141, 1338.
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Since 9 has a suitable structure to produce lasofoxifene (4)
and nafoxidine (3), the dehydroiodination of 9 was then attempt-
ed using DBU, and the desired dihydronaphthalene 11 was
exclusively obtained in good yield (Scheme 3). According to
our previous study, the double-bond migration of 11 was suc-
cessfully attained using t-BuOK in DMSO to produce a synthetic
intermediate 12 which corresponds to the common framework
for preparing 3 and 4.
During the first attempt for the direct conversion of 9 to the
common intermediate 12 using t-BuOK in usually dried DMSO,
uncharacterized over-aromatized compounds were unfortunately
synthesized; however, this conversion was finally and success-
fully attained using t-BuOK in degassed DMSO by freeze-
and-thaw cycles as shown in Scheme 4. The total syntheses of
lasofoxifene (4) and nafoxidine (3) were finally accomplished
via the successive introduction of the 2-pyrroridinoethyl moiety
onto the hydroxy group of 12 by the conventional method ac-
cording to the report of Kapil et al.,6 followed by hydrogenation
and cleavage of the protective group in the methoxy substituent
4
5
D. Lednicer, D. E. Emmert, S. C. Lyster, G. W. Duncan, J. Med.
Chem. 1969, 12, 881.
´
a) J. Barluenga, J. M. Gonzalez, P. J. Campos, G. Asensio, Angew.
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´
P. J. Campos, G. Asensio, Angew. Chem., Int. Ed. 1988, 27,
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6
R. D. Bindal, S. Durani, R. S. Kapil, N. Anand, Synthesis 1982,
405.
Published on the web (Advance View) December 2, 2006; doi:10.1246/cl.2007.40