Synthesis of non-steroidal estrogen receptor antagonists R1128 A, B, C, and D via an oxazoline-promoted iterative ortho-lithiation strategy

Article abstract of DOI:10.1246/bcsj.20110243

A concise total synthesis of non-steroidal estrogen receptor antagonists R1128 A-D (1a-1d) has been achieved using iterative ortho-lithiation of 2-(4-methoxyphenyl)-4,4- dimethyloxazoline (3) as the key reaction.

Full text of DOI:10.1246/bcsj.20110243

Short Articles
Bull. Chem. Soc. Jpn. Vol. 85, No. 1, 133-135 (2012)
133
N
O
Synthesis of Non-Steroidal Estrogen
Receptor Antagonists R1128 A, B, C,
and D via an Oxazoline-Promoted
Iterative ortho-Lithiation Strategy
tamoxifen
Tsutomu Fukuda, Koichiro Fukushima,
Susumu Sanai, and Masatomo Iwao*
R
O
OH
HO
OH
Division of Chemistry and Materials Science, Graduate
School of Engineering, Nagasaki University,
1-14 Bunkyo-machi, Nagasaki 852-8521
O
R1128 A (1a): R = CH2CH2CH3
R1128 B (1b): R = CH2CH2CH2CH3
R1128 C (1c): R = CH2CH2CH(CH3)2
R1128 D (1d): R = CH2CH2CH2CH2CH3
Received August 12, 2011
Figure 1. Tamoxifen and R1128 A-D.
E-mail: iwao@nagasaki-u.ac.jp
R
O
R
O
O
OH
A concise total synthesis of non-steroidal estrogen
receptor antagonists R1128 A-D (1a-1d) has been achieved
using iterative ortho-lithiation of 2-(4-methoxyphenyl)-4,4-
dimethyloxazoline (3) as the key reaction.
O
MeO
HO
OH
OMe
1
2
MeO
I
R
O
1st
Tamoxifen, a non-steroidal estrogen receptor antagonist,
has been employed in the chemotherapy of estrogen receptor
positive breast cancer.1 However, long-term administration of
tamoxifen frequently results in development of tumor resist-
ance to this drug. Therefore, a variety of new types of estrogen
receptor modulators have been investigated.2 In 1993, Hori
et al. of Fujisawa Pharmaceutical Co. reported the isolation of
novel non-steroidal estrogen receptor antagonists named R1128
A, B, C, and D (1a-1d) from the cultured broth of Streptomyces
sp. No. 1128.3 These compounds possess a common structural
motif of 8-alkyl-1,3,6-trihydroxyanthraquinone (Figure 1).
They exhibited varying degrees of estrogen receptor binding
activities depending on the length of alkyl groups at the
8-position. Moreover, R1128 B showed potent antitumor
activity against estrogen receptor positive human mammary
adenocarcinoma MCF-7 xenografted in nude mice. Despite
these impressive biological activities, the synthesis of 1a-1d
has not been reported. In this paper, we describe the first and
concise total synthesis of 1a-1d.
N
H
O
MeO
4
3
2nd
MeO
OMe
Scheme 1. Retrosynthetic analysis of R1128s 1.
a short synthesis of 3,4-dihydroisocoumarin natural products.8
On the basis of these results, we designed a concise synthesis
of R1128s 1 (Scheme 1). As is expected from previous
studies,4,5 1 can be derived from 7-alkylphthalides 2. The
construction of 2 will be efficiently achieved via iterative
ortho-lithiation6 of 2-(4-methoxyphenyl)-4,4-dimethyloxa-
zoline (3): 1) the initial ortho-lithiation of 3 followed by
alkylation with iodoalkane, 2) the second ortho-lithiation of
the alkylated products followed by addition to 3,5-dimeth-
oxybenzaldehyde (4).
Snieckus and co-workers reported the regioselective and
efficient synthesis of a variety of anthraquinone natural
products using the directed ortho-lithiation of N,N-diethyl-
benzamides as the key reaction.4 This strategy was extended
to the synthesis of peri-methylanthraquinone natural products
such as erythrolaccin and deoxyerythrolaccin.5 In this syn-
thesis, a silicon-protection protocol has been developed to
avoid the preferential lateral lithiation of N,N-diethyl-o-
methylbenzamides.6 On the other hand, we discovered that
the selective ortho-lithiation of 4,4-dimethyl-2-(o-tolyl)oxa-
zolines can be achieved under kinetically controlled conditions
without protecting the thermodynamically more acidic lateral
methyl group.7 This novel reaction was successfully applied to
The total synthesis of R1128 A-D (1a-1d) following this
idea is depicted in Scheme 2. ortho-Lithiation of the oxazoline
3 with sec-BuLi (1.2 equiv) in THF at ¹78 °C followed by
treatment with appropriate iodoalkanes gave the ortho-alkyl-
ated products 5a-5d in 79-86% yields.9 These compounds
were lithiated again with sec-BuLi (1.2 equiv) in THF at
¹78 °C and treated with 3,5-dimethoxybenzaldehyde (4).
Crude addition products were not isolated but subjected
to trifluoroacetic acid (TFA)-mediated lactonization10 to give
7-alkylphthalides 2a-2d in 73-90% yields. It is noteworthy
that the 3,4-dihydroisocoumarins derived from the laterally
lithiated species were not isolated in these reactions. Thus, the
lithiations of 5a-5d under sec-BuLi-THF conditions are highly
Published on the web December 30, 2011; doi:10.1246/bcsj.20110243

134
Bull. Chem. Soc. Jpn. Vol. 85, No. 1 (2012)
© 2012 The Chemical Society of Japan
O
R
O
R
O
1. sec-BuLi (1.2 equiv)
1. sec-BuLi (1.2 equiv)
N
N
THF, –78 °C, 1 h
THF, –78 °C, 1 h
O
2. R-I (1.3 equiv)
–78 °C, 1 h, then rt, 1 h
2. 3,5-dimethoxybenzaldehyde (4)
3. TFA, aq THF, rt, 24 h
MeO
MeO
MeO
5a: R = CH2CH2CH3 (83%)
3
OMe
5b: R = CH2CH2CH2CH3 (84%)
5c: R = CH2CH2CH(CH3)2 (79%)
5d: R = CH2CH2CH2CH2CH3 (86%)
MeO
2a: R = CH2CH2CH3 (73%) (69%)a
2b: R = CH2CH2CH2CH3 (84%) (67%)a
2c: R = CH2CH2CH(CH3)2 (85%) (66%)a
2d: R = CH2CH2CH2CH2CH3 (90%) (71%)a
One-pot synthesis without isolation of 5a-5d
a Yields in one-pot synthesis from 3
R
CO2H
R
O
O
OMe
R
O
OH
H2, Pd(OH)2
THF, MeOH
1. TFAA, CH2Cl2
2. CrO3, aq AcOH
AlI3, TBAI
benzene, reflux
MeO
MeO
OMe
HO
OH
MeO
OMe
O
6a: R = CH2CH2CH3 (98%)
7a: R = CH2CH2CH3 (67%)
1a: R = CH2CH2CH3 (89%)
6b: R = CH2CH2CH2CH3 (97%)
6c: R = CH2CH2CH(CH3)2 (96%)
7b: R = CH2CH2CH2CH3 (63%)
7c: R = CH2CH2CH(CH3)2 (64%)
7d: R = CH2CH2CH2CH2CH3 (54%)
1b: R = CH2CH2CH2CH3 (92%)
1c: R = CH2CH2CH(CH3)2 (82%)
1d: R = CH2CH2CH2CH2CH3 (89%)
6d: R = CH2CH2CH2CH2CH3 (97%)
Scheme 2. Total synthesis of R1128 A-D (1a-1d).
ortho-selective. More efficient transformation of 3 to 2 can
be achieved by a one-pot reaction without isolation of the
intermediates 5. In this manner, phthalides 2a-2d were
obtained after TFA-mediated lactonization in 66-71% yields.
The yields are comparable to those of the two-pot reactions
(61-77%).
washed with brine, dried over Na2SO4, and evaporated. The
residue was purified by flash chromatography over Silica Gel
60N (hexane-ethyl acetate = 3:1) to give 5. Physical and
spectroscopic data of 5 are shown in Supporting Information.
Synthesis of 7-Alkylphthalides 2. Typical Procedure.
Under an argon atmosphere, a cyclohexane-n-hexane solution
of sec-BuLi (1.04 M, 1.2 mmol) was added dropwise to a
solution of 5 (1.00 mmol) in THF (10 mL) at ¹78 °C. After
being stirred for 1 h, a solution of 3,5-dimethoxybenzaldehyde
(4) (216 mg, 1.3 mmol) in THF (3 mL) was added dropwise.
After being stirred for 1 h, the mixture was quenched with
water, allowed to warm to room temperature, and evaporated.
The products were extracted with diethyl ether and the extract
was washed with brine, dried over Na2SO4, and evaporated.
The residue was dissolved in 10 mL of a mixed solvent (THF-
H2O-TFA = 10:1.5:0.5) at room temperature. After being
stirred for 24 h, the mixture was quenched with saturated
aqueous NaHCO3 and evaporated. The products were extracted
with diethyl ether and the extract was washed with water and
brine, dried over Na2SO4, and evaporated. The residue was
purified by flash chromatography over Silica Gel 60N (hexane-
ethyl acetate = 3:1) to give 2. Physical and spectroscopic data
of 2 are shown in Supporting Information.
One-Pot Synthesis of 7-Alkylphthalides 2. Typical Pro-
cedure. Under an argon atmosphere, a cyclohexane-n-hexane
solution of sec-BuLi (0.923-1.00 M, 1.47 mmol) was added
dropwise to a solution of 3 (0.977 mmol) in THF (10 mL) at
¹78 °C. After being stirred for 1 h, an appropriate iodoalkane
(1.66 mmol) was added as a neat liquid. After being stirred for
1 h at ¹78 °C, the reaction mixture was allowed to warm to
room temperature, stirred for an additional 1 h, and recooled to
¹78 °C. A cyclohexane-n-hexane solution of sec-BuLi (0.923-
1.00 M, 1.66 mmol) was added dropwise to the reaction
mixture at ¹78 °C. After being stirred for 1 h, a solution of
3,5-dimethoxybenzaldehyde (4) (276 mg, 1.66 mmol) in THF
(3 mL) was added dropwise. After being stirred for 1 h, the
mixture was quenched with water, allowed to warm to room
temperature, and evaporated. The products were extracted with
Conversion of the phthalides 2a-2d to R1128 A-D (1a-1d)
was efficiently achieved in three steps.4,5 Hydrogenolysis of
the phthalide ring of 2a-2d using Pearlman’s catalyst11 gave
o-benzylbenzoic acids 6a-6d in nearly quantitative yields.
Friedel-Crafts cyclization of 6a-6d using trifluoroacetic
anhydride (TFAA) followed by oxidation with chromium
trioxide gave anthraquinones 7a-7d in moderate yields. Final
deprotection of all the methyl groups with aluminum triiodide12
in refluxing benzene gave R1128 A-D (1a-1d) in good yields.
An attempted deprotection of 7a with boron tribromide
produced a complex mixture of partially demethylated anthra-
1
quinones. H and 13C NMR spectra of 1a-1d thus synthesized
were shown to be identical with those reported for the natural
products.3b
In conclusion, we have achieved a concise total synthesis of
R1128 A-D (1a-1d) using oxazoline-promoted iterative ortho-
lithiation of 3 as the key reaction. The average total yield is
approximately 36%. The synthetic route described herein is
suitable to provide R1128 analogues with a variety of peri-
alkyl groups for structure-activity relationship studies.
Experimental
Synthesis of ortho-Alkyloxazolines 5. Typical Procedure.
Under an argon atmosphere, a cyclohexane-n-hexane solution
of sec-BuLi (1.02 M, 6.00 mmol) was added dropwise to a
solution of 313 (1.03 g, 5.00 mmol) in THF (50 mL) at ¹78 °C.
After being stirred for 1 h, an appropriate iodoalkane (6.50
mmol) was added as a neat liquid. After being stirred for 1 h at
¹78 °C, the reaction mixture was allowed to warm to room
temperature and stirred for an additional 1 h. The mixture was
quenched with saturated aqueous NH4Cl and evaporated. The
products were extracted with diethyl ether, and the extract was

T. Fukuda et al.
Bull. Chem. Soc. Jpn. Vol. 85, No. 1 (2012)
135
diethyl ether and the extract was washed with brine, dried
over Na2SO4, and evaporated. The residue was dissolved in
10 mL of a mixed solvent (THF-H2O-TFA = 10:1.5:0.5) at
room temperature. After being stirred for 24 h, the mixture was
quenched with saturated aqueous NaHCO3 and evaporated. The
products were extracted with diethyl ether and the extract was
washed with brine, dried over Na2SO4, and evaporated. The
residue was purified successively by flash chromatography over
Silica Gel 60N (hexane-ethyl acetate = 7:1) and flash chro-
matography over Silica Gel 60N (toluene-ethyl acetate = 20:1)
to give 2.
Synthesis of Benzylbenzoic Acids 6. Typical Procedure.
Under a hydrogen atmosphere, a mixture of phthalide
2 (1.50 mmol), Pearlman’s catalyst (514 mg), THF (7.5 mL),
and methanol (7.5 mL) was vigorously stirred overnight at
room temperature. The mixture was passed through a pad of
Celite and the filtrate was evaporated. The residue was purified
by column chromatography over Silica Gel 60N (hexane-ethyl
acetate = 2:1) to give 6. Physical and spectroscopic data of
6 are shown in Supporting Information.
acidified with 2 M aqueous HCl and extracted with ethyl
acetate. The organic phase was extracted with 2 M aqueous
NaOH and the extract was washed with ethyl acetate and
acidified with concentrated HCl. The product was re-extracted
with ethyl acetate and the extract was dried over Na2SO4 and
evaporated. The residue was purified by column chromatog-
raphy over Silica Gel 60N (dichloromethane-ethyl acetate =
10:1) to give 1. Physical and spectroscopic data of 1 are shown
in Supporting Information.
Supporting Information
1
Physical and spectroscopic data including H and 13C NMR
spectra of all compounds synthesized in this work. This
material is available free of charge on the web at http://
www.csj.jp/journals/bcsj/.
References
1
a) S. Litherland, I. M. Jackson, Cancer Treat. Rev. 1988, 15,
183. b) M. Clemons, S. Danson, A. Howell, Cancer Treat. Rev.
2002, 28, 165.
Synthesis of Anthraquinones 7. Typical Procedure.
Under an argon atmosphere, trifluoroacetic anhydride (1.99
mmol) was added as a neat liquid to a solution of benzoic
acid 6 (0.302 mmol) in dichloromethane (12.9 mL) at 0 °C. The
reaction mixture was allowed to warm to room temperature and
stirred for 5 h. The mixture was quenched with methanol and
the solvent was evaporated. To the residue was added saturated
aqueous NaHCO3 and the mixture was extracted with dichloro-
methane. The extract was dried over Na2SO4 and evaporated.
To the crude product was added a solution of CrO3 (0.338
mmol) and water (several drops) in acetic acid (7.6 mL). After
being stirred for 3.5 h at room temperature, the mixture was
evaporated. To the residue was added saturated aqueous
NaHCO3 and the mixture was extracted with dichloromethane.
The extract was passed through a pad of Celite. The filtrate was
dried over Na2SO4 and evaporated. The residue was purified
by column chromatography over Silica Gel 60N to give 7.
Physical and spectroscopic data of 7 are shown in Supporting
Information.
Synthesis of R1128s 1. Typical Procedure. Under an
argon atmosphere, a mixture of aluminum (foil, 1.14 mmol),
iodine (0.859 mmol), and benzene (5.0 mL) was refluxed for
1.5 h and then cooled to room temperature. To the suspension
was added a solution of anthraquinone 7 (84.7 ¯mol) and
tetrabutylammonium iodide (4.9 ¯mol) in benzene (3 mL).
After being refluxed for 12 h, the mixture was cooled to
room temperature and quenched with water. The product was
2
3
V. C. Jordan, A. M. H. Brodie, Steroids 2007, 72, 7.
a) Y. Hori, Y. Abe, M. Ezaki, T. Goto, M. Okuhara, M.
Kohsaka, J. Antibiot. 1993, 46, 1055. b) Y. Hori, S. Takase, N.
Shigematsu, T. Goto, M. Okuhara, M. Kohsaka, J. Antibiot. 1993,
46, 1063. c) Y. Hori, Y. Abe, M. Nishimura, T. Goto, M. Okuhara,
M. Kohsaka, J. Antibiot. 1993, 46, 1069.
4
S. O. De Silva, M. Watanabe, V. Snieckus, J. Org. Chem.
1979, 44, 4802.
5
6
R. J. Mills, V. Snieckus, J. Org. Chem. 1989, 54, 4386.
R. J. Mills, N. J. Taylor, V. Snieckus, J. Org. Chem. 1989,
54, 4372.
7
9069.
8
5117.
9
N. Tahara, T. Fukuda, M. Iwao, Tetrahedron Lett. 2002, 43,
N. Tahara, T. Fukuda, M. Iwao, Tetrahedron Lett. 2004, 45,
ortho-Lithiation of 3 with n-BuLi in diethyl ether was
originally reported by Gschwend and Hamdan, see: H. W.
Gschwend, A. Hamdan, J. Org. Chem. 1975, 40, 2008. We
observed the reaction of the ortho-lithio species derived from 3
with 1-iodopropane in diethyl ether was quite sluggish to give 5a
in only 6% yield (0 °C, 4 h).
10 Y. Kurosaki, T. Fukuda, M. Iwao, Tetrahedron 2005, 61,
3289.
11 W. M. Pearlman, Tetrahedron Lett. 1967, 8, 1663.
12 A. T. Kreipl, C. Reid, W. Steglich, Org. Lett. 2002, 4, 3287.
13 C. E. Anson, C. S. Creaser, A. V. Malkov, L. Mojovic,
G. R. Stephenson, J. Organomet. Chem. 2003, 668, 101.