A convenient synthetic method of a 5,7-diarylcyclopenteno-[1,2-b]pyridine-6-carboxylate: A key intermediate for potent endothelin receptor antagonists

Article abstract of DOI:10.1016/S0968-0896(02)00261-4

A convenient synthetic method of 4, a key intermediate for a new class of endothelin receptor antagonists, was developed. Racemic 4 was synthesized from quinolinic anhydride in 13.4% overall yield without chromatographic purification.

Full text of DOI:10.1016/S0968-0896(02)00261-4

Bioorganic & Medicinal Chemistry 10 (2002) 3437–3444
A Convenient Synthetic Method of a 5,7-Diarylcyclopenteno-
[1,2-b]pyridine-6-carboxylate:A Key Intermediate for Potent
Endothelin Receptor Antagonists
Kenji Niiyama,* Takashi Yoshizumi, Hirobumi Takahashi, Akira Naya,
Norikazu Ohtake, Takehiro Fukami, Toshiaki Mase,
Takashi Hayama and Kiyofumi Ishikawa
Tsukuba Research Institute, Banyu Pharmaceutical Co., Ltd., 3 Okubo, Tsukuba,
Ibaraki 300-2611, Japan
Received 30 April 2002; accepted 25 June 2002
Abstract—A convenient method for the synthesis of the title intermediate 4 was described. The key steps of this synthesis involved:
(1) regioselective addition reaction of arylzinc reagent to quinolic anhydride in 42% isolated yield, (2) conversion of a ketoacid 7 to
an enone 14, which was achieved in 65% yield by intramolecular Knoevenagel reaction of b-ketoester generated by condensation of
an acid imidazolide 11 with an ester enolate, followed by dehydration assisted with silica gel, and (3) stereoselective reduction of an
allyl alcohol 15 in 75% yield with zinc under acidic conditions. This synthesis enabled us to provide hundreds of grams of 4 without
chromatographic purification.
# 2002 Elsevier Science Ltd. All rights reserved.
Introduction
was limited by difficulty on the supply of the key inter-
Endothelin-1 (ET-1),1 and its closely related isopeptides
(ET-2, ET-3) were identified in 1988 as potent vaso-
constrictor peptides consisting of 21 amino acids. Since
peptide endothelin receptor antagonists such as
BQ-1232 exhibited their clinical potential in endothelin-
mediated disorders, many pharmaceutical companies
have extensively pursued studies directed toward the
development of non-peptide endothelin antagonists as
therapeutic agents.3
mediate 4 in a facile manner. Therefore, establishment
of a convenient and practical synthetic method of 4 was
essential.4 In this paper, we describe a feasible approach
by improving regio- and stereo-selectivity at key reac-
tion steps shown in Scheme 1.
We discovered a 6-carboxy-5,7-diarylcyclopenteno[1,2-b]
pyridine derivative 1 to be a novel lead structure for a
potent endothelin receptor antagonist (Fig. 1). Through
the derivatization of 1, we discovered that introduction
of functional groups into the a-position of the 4-meth-
oxyphenyl group changed biological properties without
losing the binding affinities. Actually, we identified
compound 2 and 3 with highly potent in vivo efficacy in
a mouse model.4 However, extensive derivatization of 1
*Corresponding author. Tel.: +81-298-77-2220; fax: +81-298-77-
2027; e-mail: niiymakj@banyu.co.jp
Figure 1. 6-Carboxy-5,7-diarylcyclopenteno[1,2-b]pyridine derivatives.
0968-0896/02/$ - see front matter # 2002 Elsevier Science Ltd. All rights reserved.
PII: S0968-0896(02)00261-4

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K. Niiyama et al. / Bioorg. Med. Chem. 10 (2002) 3437–3444
Scheme 1. Retrosynthetic analysis of 4.
Results and Discussion
the loss of the regioselectivity in the reaction was con-
sidered to be due to the high nucleophilicity of these
arylmetal reagents, we examined the reaction with the
corresponding arylzinc reagent that is known to have
lower nucleophilicity. As expected, the zinc reagent,
prepared in situ from the corresponding lithium reagent
with zinc chloride, improved the regioselectivity (7/
8=6:1). The desired isomer 7 was exclusively obtained
as a crystalline solid in 42% yield, and the yield was
reproducible (40–50% yield) even in a kilogram-scale
preparation.
Retrosynthetic analysis of 4 suggested a potentially fea-
sible approach for the diastereoselective synthesis
(Scheme 1). This approach needed optimization and
improvement of: (1) regioselectivity of the addition
reaction of an arylmetal reagent to quinolic anhydride
5, (2) reaction conditions of the conversion of the
ketoacid 7 into the enone 14, and (3) stereoselectivity of
the hydrogenation of the allyl alcohol system in 15. In
addition, we also considered to use no chromatography
in the process for the preparation of a large amount of
the intermediate.
For the conversion of the ketoacid 7 to the enone 14, we
adopted a strategy via a b-keto ester 12.7 The reaction
of the corresponding acid chloride or acid imidazolide
11 with a magnesium salt of malonic acid monoester
under Masamune’s condition8 did not produce the
desired b-keto ester 12, probably due to the low reac-
tivity of the acid chloride or the acid imidazolide. Since
the acid imidazolide 11 was obtained as a crystalline
solid in high yield, further investigation was carried out
using 11. Treatment of the imidazolide 11 with 1.2
equivalents of an enolate of tert-butyl acetate unexpect-
edly provided a cyclized product 13 in good yield. Puri-
fication of the product 13 by column chromatography
on silica gel or alumina was unsuccessful because of its
instability of the product under both weak acidic and
basic conditions. When the crude material obtained via
a usual work up was treated with silica gel in chloro-
form, the dehydration occurred smoothly to provide the
desired enone 14 in good yield. As a result, treatment of
the acid imidazolide 11 with 1.5 equivalents of the
lithium enolate of tert-butyl acetate at ꢀ70 to ꢀ60 ꢁC
followed by dehydration assisted with silica gel repro-
ducibly produced the enone 14 in 65% yield as a crys-
talline solid. The proposed mechanism of the reaction is
shown in Figure 2; (1) the acid imidazolide moiety of 11
reacted with the enolate of tert-butyl acetate to produce
the b-keto ester 12, (2) an acidic proton of 12 was
abstracted by an excess amount of the enolate anion to
To begin with, the regioselective addition of the aryl
moiety to the anhydride 5 was investigated. The addi-
tion reaction of 2-benzyloxy-4-methoxyphenyl magne-
sium bromide or the corresponding lithium reagent to 5
gave a mixture of regioisomer 7 and 8 in 65% (7/8=4:3)
and 36% yield (7/8=3:2), respectively (Table 1).5,6 Since
Table 1. Regioselective addition of arylmetal reagents to quinolic
anhydride 5
X
Yield (%)
Ratio (7:8)
Li
65
36
40
4:3
3:2
6:1
—
MgBr
ZnCla
Ti(Oi-Pr)3
b
No reaction
aPrepared from the corresponding lithium reagent with ZnCl2.
bPrepared from the corresponding lithium reagent with TiCl(Oi-Pr)3.

K. Niiyama et al. / Bioorg. Med. Chem. 10 (2002) 3437–3444
3439
Figure 2. Mechanism of the formation of 14.
3,4-methylenedioxyphenylmagnesium bromide to the
enone 14 successfully produced an allyl alcohol 15 in
91% yield.
Stereoselective reduction of the allyl alcohol system in
15 was also crucial in this synthesis. In fact, the catalytic
hydrogenation of 15 in the presence of 10% Pd on car-
bon gave a saturated alcohol 20 in 82% yield as shown
in Figure 3. Since it was known that the deoxygenation
of a simple allyl alcohol system was achieved by using
zinc,9 we applied the procedure to the more complex
system of 15. The results are summarized in Table 2.
Reduction with 3 equivalents of zinc in the presence of 5
equivalents of acetic acid resulted in the production of a
deoxygenated compound 16 in 10% yield, while 64% of
the starting material 15 was recovered. In contrast, the
use of other reducing agents such as SnCl2 and Fe did
Figure 3. Catalytic hydrogenation of the intermediate 15.
generate the a-anion of 12, (3) the anion intramolecu-
larly attacked the carbonyl group to provide the labile
b0-hydroxy-b-ketoester 13, and (4) 13 was dehydrated in
the presence of silica gel to give 14. The addition of a
Table 2. Results on the reduction of 15 with various reducing agents
Reagent
Solvent
Additive
Temperature (ꢁC)
Results
Zn (3 equiv)
SnCl2 (3 equiv)
SnCl2 (3 equiv)
Fe (3 equiv)
Mg (3 equiv)
Zn (3 equiv)
Zn (7.5 equiv)
Zn (7.5 equiv)
THF
THF–MeOH (1:1)
MeOH
AcOH (5 equiv)
None
1 N HCI (5 equiv)
1 N HCI (5 equiv)
None
4 N HCI (5 equiv)
4 N HCI (9 equiv)
4 N HCI (9 equiv)
0 to rt
rt to reflux
15: 64%, 16: 10%
No reaction
No reaction
No reaction
No reaction
rt
70
70
0
0
0
MeOH
THF–MeOH (1:1)
THF
THF
17: 33%, 16 + 18: 24%
16: 0%, 17: 56%, 18: 24%
16: 0%, 17: 79%, 18: 14%
THF–EtOH (1:1)
aA mixture of trans–trans isomer 19 and cis–trans isomers.

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K. Niiyama et al. / Bioorg. Med. Chem. 10 (2002) 3437–3444
Scheme 2. Synthesis of the key intermediate 4. Reagents and conditions: (a) n-BuLi, 4-bromo-3-benzyloxyanisole 6, THF, ꢀ60 ꢁC, ZnCl2, 40 ꢁC; (b)
CDI, DMF, rt; (c) (1) CH3CO2t-Bu, LDA, ꢀ70 ꢁC, (2) SiO2, CHCl3, rt; (d); 3,4-(methylenedioxy)phenylmagnesium bromide, THF, ꢀ78 ꢁC; (e) Zn,
4 N HCl in dioxane, THF, EtOH, 10 ꢁC; (f) tert-BuOK, tert-BuOH, 60 ꢁC; (g) H2, Pd/C, THF, MeOH, rt.
not lead to the deoxygenated products. In addition, it
was revealed that the acid used with zinc was crucial to
the course of the reaction. When 15 was treated with 3
equivalents of zinc in the presence of 5 equivalents of
hydrogen chloride, the deoxygenation and reduction of
the double bond occurred simultaneously to produce
the cis–cis isomer 17 in 33% yield accompanied by 16, a
trans–trans isomer 19 and cis–trans isomers. Although
the hydrogenation of 15 was completed with an
increased amount of zinc (7.5 equiv) and hydrogen
chloride (9 equiv), the ratio of the cis–cis isomer 17 to
the other isomers was not satisfactory (5:2). Optimiza-
tion of the reaction solvent revealed that using a mix-
ture of THF and EtOH (1:1) as a solvent resulted in
improvement in the ratio of 17 to 18 up to 5:1 as well as
the yield (79%). When the deoxygenated intermediate
16 was treated with zinc powder (5 equiv) in the pres-
ence of hydrogen chloride (5 equiv), a mixture of the
hydrogenated compound 17 and 18 was obtained in
98% yield in a ratio of 5:1. It is interesting to note that
the thermodynamically less stable isomer 17 was
obtained as a major product. Although the detailed
mechanism of the reaction is not clear, the results sug-
gested that the deoxygenation occurred at first to give
16, in which the double bond may migrate via a 1,3
hydride shift, and then the double bond was reduced
with the residual zinc. As a result, deoxygenation and
hydrogenation of 15 were simultaneously achieved
under mild conditions and the desired isomer 17 was
exclusively isolated by crystallization of the crude mix-
ture in 75% yield.
treatment with tert-BuOK in dioxane–tert-BuOH (1:1)
at 60 ꢁC. Finally, the catalytic hydrogenation of 19 in
the presence of 10% Pd on charcoal at 3 kg/cm2 of
pressure provided the key intermediate 4 in 89% yield.
In summary, we successfully developed a convenient
method for the synthesis of the intermediate 4. The key
points of the method are as follows: (1) regioselectivity
of the addition reaction of the aryl moiety to quinolic
anhydride was improved by using arylzinc reagent gen-
erated in situ to provide the desired ketoacid 7 in 42%
yield, (2) cyclization of 7 was achieved in 65% yield to
give the enone 14 by the treatment of the corresponding
acid imidazolide 11 with the ester enolate followed by
dehydration assisted with silica gel and (3) stereo-
selective hydrogenation of the allyl alcohol system in 15
was accomplished by using zinc in the presence of
hydrogen chloride to afford the cis–cis isomer 17 in 75%
yield. Through the method we developed, 4 was
obtained in six steps with 13.4% overall yield from qui-
nolic anhydride 5 without chromatographic purification
(Scheme 2). This synthetic method enables us to do
extensive derivatization of this class of compounds for
potent endothelin receptor antagonists. The results of
the derivatization will be reported in the near future.
Experimental
General
All reagents and solvents were of commercial quality
and were used without further purification unless
otherwise noted. Melting points were determined with a
17 was completely epimerized to a thermodynamically
more stable trans–trans isomer 19 in 93% yield by the

K. Niiyama et al. / Bioorg. Med. Chem. 10 (2002) 3437–3444
3441
Yanaco MP micromelting point apparatus and were not
1
3-(2-Benzyloxy-4-methoxybenzoyl)-2-pyridinecarboxylic
acid (8). To a solution of the methyl ester 10 (4.66 g,
mmol) in MeOH (90 mL) and dioxane (10 mL) was
added 6 N NaOH (9.0 mL), and the mixture was stirred
at room temperature overnight. After removal of
MeOH under reduced pressure, the residual solution
was neutralized with 2 N HCl (30 mL). The resulting
precipitate was collected by filtration, washed with ace-
tone followed by Et2O, and dried under reduced pres-
sure to give the corresponding carboxylic acid 8 (5.27 g,
95% yield). mp: 165–166 ꢁC (dec.); MS m/z 364
(M+H)+. Anal. calcd for C21H17NO5: C, 69.41; H,
4.72; N, 3.86. Found: C, 69.76; H, 4.59; N, 3.82.
corrected. H NMRspectra were recorded on a Varian
Gemini-300 instrument at 300 MHz. Chemical shifts
were reported in parts per million as d units relative to
tetramethylsilane as an internal standard. Mass spectra
were recorded with fast atom bombardment (FAB)
ionization on a JEOL JMS-SX 102A spectrometer. Thin
layer chromatography was performed with E. Merck
Kieselgel 60 F254 plates (0.25 mm) and visualized with
UV light or phosphomolybdic acid. Column chroma-
tography was performed on Wako gel C-300.
3-Benzyloxy-4-bromoanisole (6). To
a solution of
2-bromo-5-methoxyphenol7 (2330 g, 11.5 mol) in ace-
tone (12.0 L) were added anhydrous K2CO3 (1590 g,
11.5 mol) and benzyl bromide (1970 g, 11.5 mol), and
the mixture was stirred at 60 ꢁC for 12 h. After the
reaction mixture was cooled to room temperature, the
insoluble material was removed by filtration. The filtrate
was concentrated and the residual oil was distilled under
2-(2-Benzyloxy-4-methoxybenzoyl)-3-pyridinecarboxylic
acid (7). To a solution of 4-bromo-3-benzyloxyanisole 6
(1050 g, 3.58 mol) in THF (10 L) was added a 1.58 M
solution of n-butyllithium in hexane (3.0 L, 4.74 mol) at
ꢀ60 to ꢀ65 ꢁC, and the mixture was stirred at ꢀ65 ꢁC
for 1 h. To that solution was added ZnCl2 (683 g, 5.01
mol) at ꢀ65 ꢁC, and the resulting mixture was warmed
to 30 ꢁC over 1 h. To the mixture was added quinolic
anhydride (534 g, 3.58 mol), and the mixture was stirred
at 40 ꢁC overnight. The mixture was quenched with 2 N
HCl (5.0 L), and was stirred at room temperature for 2
days. The resulting precipitate was collected by filtra-
tion, washed with 2 N HCl (2.0 L) followed by acetone
(2.0 L) and Et2O (2.0 L), and dried under reduced pres-
sure to give 7 (546 g, 42% yield). mp: 213–214 ꢁC (dec.);
reduced pressure (1–2 mmHg, 160–170 ꢁC) to provide 6
1
(2100 g, 62% yield). H NMR(CDCl ): d 3.75 (s, 3H),
3
5.12 (s, 2H), 6.40 (dd, J=2.7, 8.7 Hz, 1H), 6.52 (d,
J=2.7 Hz, 1H), 7.22–7.53 (m, 5H), 7.42 (d, J=8.7 Hz,
1H); MS m/z 293 (M+H)+.
3-(2-Benzyloxy-4-methoxybenzoyl)-2-(methoxycarbonyl)-
pyridine (9) and 2-(2-Benzyloxy-4-methoxybenzoyl)-3-
(methoxycarbonyl)pyridine (10). To a solution of 5
(12.37 g, 42.2 mmol) in THF (80 mL) was added a
1.66 M solution of n-butyllithium in hexane (25.4 mL,
42.2 mmol) at ꢀ78 ꢁC, and the mixture was stirred at
the same temperature for 1 h. To a solution of quino-
linic anhydride (6.29 g, 42.2 mmol) in THF (210 mL)
was added the solution described above at ꢀ78 ꢁC.
After being stirred for 30 min, the mixture was quen-
ched with 1 N HCl (200 mL), and was extracted with
EtOAc (2ꢂ300 mL). The organic layer was washed with
brine, dried over Na2SO4 and concentrated. To a solu-
tion of the residue in CH2Cl2 (17 mL) and MeOH (83
mL) were added 4-(dimethylamino)pyridine (733 mg,
6.00 mmol) and 1-[3-(dimethylamino)propyl]-3-ethyl-
carbodiimide hydrochloride (9.71 g, 50.7 mmol) at 0 ꢁC,
and the mixture was stirred at room temperature over-
night. The reaction mixture was washed with saturated
NaHCO3 solution, and the aqueous layer was extracted
with CH2Cl2. The combined organic layer was washed
with brine, dried over MgSO4, and concentrated. The
regioisomers were separated by column chromato-
graphy on silica gel to give the methyl ester 9 (5.74 g,
36%) and 10 (4.66 g, 29%). 9: 1H NMR(CDCl 3) d 3.76
(s, 3H), 3.86 (s, 3H), 4.67 (s, 2H), 6.43 (d, J=2.3 Hz,
1H), 6.65 (dd, J=2.3, 8.8 Hz, 1H), 6.90–6.93 (m, 2H),
6.97 (dd, J=4.9, 7.9 Hz, 1H), 7.19–7.28 (m, 3H), 7.80
(dd, J=1.6, 7.9 Hz, 1H), 8.17 (d, J=8.8 Hz, 1H), 8.47
(dd, J=1.6, 4.9 Hz, 1H); HRMS calcd for C22H20NO5
(M+H)+: 378.1341. Found 378.1349. 10: 1H NMR
(CDCl3) d 3.79 (3H, s), 3.86 (3H, s), 4.74 (2H, s), 6.44
(1H, d, J=2.3 Hz), 6.64 (dd, J=2.3, 8.8 Hz, 1H), 6.926.95
(m, 2H), 7.20 (dd, J=4.8, 7.8 Hz, 1H), 7.23–7.29 (m, 3H),
7.57 (dd, J=1.7, 7.8 Hz, 1H), 8.04 (d, J=8.8 Hz, 1H),
8.41 (dd, J=1.7, 4.8 Hz, 1H); HRMS calcd for
C22H20NO5 (M+H)+: 378.1341. Found 378.1335.
1H NMR(CD OD) d 3.88 (s, 3H), 4.73 (s, 2H), 6.61 (d,
3
J=2.3 Hz, 1H), 6.72 (dd, J=2.3 and 8.9 Hz, 1H), 6.92–
7.00 (m, 2H), 7.12 (dd, J=4.9, 7.8 Hz, 1H), 7.21–7.30
(m, 3H), 7.95 (dd, J=1.7, 7.8 Hz, 1H), 8.07 (d, J=8.9
Hz, 1H), 8.38 (dd, J=1.7, 4.9 Hz, 1H), MS m/z 364
(M+H)+. Anal. calcd for C21H17NO5: C, 69.41; H,
4.72; N, 3.86. Found: C, 69.15; H, 4.61; N, 3.78.
2-(2-Benzyloxy-4-methoxybenzoyl)-3-(1-imidazolyl)carb-
onylpyridine (11). To an ice-cooled solution of 7 (2160
g, 5.94 mol) in DMF (3.0 L) was added carbonyldiimi-
dazole (1200 g, 7.40 mol), and the mixture was stirred at
room temperature for 2.5 h. The mixture was poured
into ice-cooled water (20.0 L), and the resulting pre-
cipitate was collected by filtration, washed with water
(2.0 L) followed by diethyl ether (2.0 L), and dried at
50 ꢁC under reduced pressure (3–5 mmHg) to give 11
(2140 g, 87% yield). mp: 167–169 ꢁC (dec.); H NMR
1
(CDCl3); d 3.78 (s, 3H), 4.46 (d, J=10.2 Hz, 1H), 4.76
(d, J=10.2 Hz, 1H), 6.36 (d, J=8.5 Hz, 1H), 6.41 (dd,
J=2.2, 8.5 Hz, 1H), 6.45 (d, J=2.2 Hz, 1H), 6.93–6.97
(m, 2H), 7.14 (brs, 1H), 7.19 (dd, J=4.8, 7.8 Hz, 1H),
7.277.34 (m, 3H), 7.46 (br s, 1H), 7.53 (dd, J=1.5, 7.8
Hz, 1H), 8.03 (br s, 1H), 8.73 (dd, J=1.5, 4.8 Hz, 1H);
+
.
MS m/z 426 (M+H) . Anal. calcd for C24H19N3O4
0.15H2O: C, 69.27; H, 4.67; N, 10.10. Found: C, 69.11;
H, 4.59; N, 10.08.
7-(2-Benzyloxy-4-methoxyphenyl)-6-tert-butoxycarbonyl-
7-hydroxy-5-oxocyclopenteno[1,2-b]pyridine (13). To a
solution of diisopropylamine (0.103 mL, 0.73 mmol) in
THF (1.0 mL) was added a 1.59 M solution of n-butyl-
lithium in hexane (0.46 mL, 0.73 mmol) at ꢀ78 ꢁC, and
the mixture was stirred at 0 ꢁC for 15 min. To that

3442
K. Niiyama et al. / Bioorg. Med. Chem. 10 (2002) 3437–3444
solution was added tert-butyl acetate (0.104 mL, 0.77
mmol) at ꢀ78 ꢁC, and the mixture was stirred at the
same temperature for 30 min. To that solution was
added a solution of 11 (202 mg, 0.49 mmol) in THF (2.4
mL) at ꢀ78 ꢁC, and the mixture was stirred at the same
temperature for additional 30 min. The mixture was
quenched with saturated NH4Cl solution, and was
extracted with EtOAc. The organic layer was washed
with brine, dried over MgSO4, and concentrated to give
the fused alcohol 13 (220 mg). 1H NMR(CDCl 3) d 1.47
(s, 9H), 3.80 (s, 3H), 4.13 (s, 1H), 4.52 (d, J=10.8 Hz,
1H), 4.76 (d, J=10.8 Hz, 1H), 6.44 (d, J=2.3 Hz, 1H),
6.62 (dd, J=2.3, 8.6 Hz, 1H), 6.78 (dd, J=1.2, 7.8 Hz,
1H), 7.17–7.25 (m, 5H), 7.67 (dd, J=1.5, 7.8 Hz, 1H),
7.85 (d, J=8.7 Hz, 1H), 8.71 (dd, J=1.2, 1.5 Hz, 1H);
MS m/z 462 (M+H)+.
THF (650 mL, 1.52 mol) prepared from 4-bromo-1,2-
(methylenedioxy)benzene (382 g, 1.90 mol) and magne-
sium turnings (48.6 g, 2.00 mol) at ꢀ78 ꢁC, and the
mixture was stirred at the same temperature for 15 min.
The mixture was quenched with saturated NH4Cl solu-
tion (4 L), and was extracted with EtOAc (3ꢂ5.0 L).
The combined organic layer was washed with brine,
dried over Na2SO4 and concentrated. The residue was
crystallized from hexane–EtOAc (5:1) to give 15 (542 g,
ꢁ
1
91% yield). mp: 151–152 C; H NMR(CDCl ) d 1.17
3
(s, 9H), 3.85 (s, 3H), 4.40 (br s, 1H), 5.06 (s, 2H), 5.89 (s,
2H), 6.37–6.49 (br s, 1H), 6.65–6.67 (m, 2H), 6.86–6.93
(br s, 1H), 7.09 (dd, J=4.9, 7.6 Hz, 1H), 7.11 (br s, 1H),
7.21–7.27 (m, 5H), 7.32–7.42 (br s, 1H), 7.51 (dd,
J=1.8, 7.6 Hz, 1H), 8.47 (dd, J=1.8, 7.9 Hz, 1H); MS
+
.
m/z 566 (M+H) . Anal. calcd for C27H25NO7 0.25
hexane: C, 72.62; H, 5.92; N, 2.39. Found: C, 72.89; H,
5.62; N, 2.46.
The resulting crude material described above was dis-
solved in CHCl3 (5 mL), and SiO2 (5 mL) was added
to the solution. After being vigorously stirred at
room temperature overnight, the SiO2 was filtered off,
and washed with EtOAc (30 mL). The filtrate and
washings were combined and concentrated. The
residue was washed with hexane–EtOAc (10:1, 10 mL)
to yield enone 14 as an orange solid (184 mg, 85%
yield).
Reduction of 15 with zinc in the presence of 9 equivalents
of hydrogen chloride. To a suspension of 15 (3.34 g,
5.91 mmol) and zinc powder (2.90 g, 44.4 mmol) in
THF (30 mL) and EtOH (30 mL) was added dropwise a
4 N solution of HCl in dioxane (13.3 mL) at 0 ꢁC. After
being stirred at 0 ꢁC for 1 h, the mixture was neutralized
with saturated NaHCO3 solution. The insoluble mate-
rial was removed by filtration and the filtrate was
extracted with CH2Cl2. The organic layer was washed
with brine, dried over MgSO4, and concentrated. The
residue was crystallized from hexane–EtOAc (1:1) to
give 17 (2.48 g, 76% yield). The filtrate was con-
centrated, and the residue was purified by column
chromatography on silica gel to provide the second crop
of 17 (0.10 g, 3% yield) and an inseparable mixture 18
(0.45 g, 14% yield) containing the cis–trans isomers and
7-(2-Benzyloxy-4-methoxyphenyl)-6-tert-butoxycarbonyl-
5-oxocyclopenta-1,3-dieno[2,1-b]pyridine (14). To a solu-
tion of diisopropylamine (586 mL, 4.18 mol) in THF
(3.8 L) was added a 1.54 M solution of n-butyllithium in
hexane (2.71 L, 4.17 mol) at ꢀ70 ꢁC, and the mixture
was stirred at the same temperature for 1 h. To that
solution was added tert-butyl acetate (580 mL, 4.30
mol) at ꢀ70 ꢁC, and the mixture was stirred at the same
temperature for 1 h. To a solution of 11 (1150 g, 2.78
mol) in THF (10.0 L) was added the enolate solution
described above via canula at ꢀ70 to ꢀ60 ꢁC. After
being stirred at ꢀ70 ꢁC for 30 min, the mixture was
quenched with saturated NH4Cl solution (500 mL).
After being warmed to room temperature, the mixture
was extracted with EtOAc (12 L). The organic layer was
washed with brine, dried over Na2SO4, and concentrated.
To a solution of the residue in CHCl3 (5.0 L) was added
silica gel (Merck 7734, 2.0 L), and the mixture was
stirred at room temperature overnight. The silica gel
was filtered off, and washed with EtOAc (5.0 L). The
filtrate and washings were combined and concentrated.
The reside was crystallized from MeOH to give 14 (800
g, 65% yield). mp: 147–148 ꢁC; 1H NMR(CDCl 3) d
1.35 (s, 9H), 3.84 (s, 3H), 5.09 (s, 2H), 6.62 (d, J=2.3
Hz, 1H), 6.67 (dd, J=2.3, 8.6 Hz, 1H), 7.22 (dd, J=5.3,
7.4 Hz, 1H), 7.24 (brs, 5H), 7.56 (d, J=8.6 Hz, 1H),
7.78 (dd, J=1.5, 7.4 Hz, 1H), 8.55 (dd, J=1.5, 5.3 Hz,
1H); MSm/z 444 (M+H)+. Anal. calcd for C27H25NO5:
C, 73.12; H, 5.68; N, 3.16. Found: C, 73.19; H, 5.71; N,
3.18.
1
the trans–trans isomer 19 in a ratio of 7:3 by H NMR.
Reduction of 15 with zinc via an intermediate 16. To a
suspension of 15 (730 mg, 1.29 mmol) and zinc powder
(253 mg, 3.87 mmol) in THF (10 mL) was added AcOH
(0.390 mL, 6.81 mmol) at 0 ꢁC. After being stirred at the
same temperature for 1 h, the mixture was neutralized
with saturated NaHCO3 solution, and was extracted
with EtOAc. The organic layer was washed with brine,
dried over MgSO4, and concentrated. The residue was
purified by column chromatography on silica gel eluting
with 33% EtOAc/hexane to give the deoxy product 16
(73 mg, 10% yield) and the starting material 15 (465 mg,
64% recovery). 16: MSm/z 550 (M+H)+.
To a suspension of 16 (73 mg, 0.13 mmol) and zinc
powder (43 mg, 0.65 mmol) in THF (2.0 mL) was added
4 N HCl in dioxane (0.17 mL, 0.68 mmol) at 0 ꢁC, and
the mixture was stirred at the same temperature for 30
min. The mixture was neutralized with saturated
NaHCO3 solution, and was extracted with EtOAc. The
organic layer was washed with brine, dried over MgSO4,
and concentrated. The residue (69 mg) was elucidated to
be a mixture of 17 and 18 in a ratio of 5:1 by 1H NMR.
7-(2-Benzyloxy-4-methoxyphenyl)-6-tert-butoxycarbonyl-
5-(3,4-methylenedioxyphenyl)-5-hydroxycyclopenta-1,3-
dieno[2,1-b]pyridine (15). To a solution of the enone 14
(467 g, 1.05 mol) in THF (3.0 L) was added a 2.34 M solu-
tion of (3,4-methylenedioxyphenyl)magnesium bromide in
(5RS,6RS,7SR)- 7-(2-Benzyloxy-4-methoxyphenyl)-6-tert-
butoxycarbonyl-5-(3,4-methylenedioxyphenyl)cyclopenteno-
[1,2-b]pyridine (17). To a stirred suspension of 15 (377g,

K. Niiyama et al. / Bioorg. Med. Chem. 10 (2002) 3437–3444
3443
667 mmol) and zinc powder (327 g, 5.00 mol) in THF
(2.0 L) and EtOH (2.0 L) was added 4 N HCl in dioxane
(1.5 L) below 10 ꢁC over 1.5 h. After the addition was
completed, the mixture was neutralized with saturated
Na2CO3 solution (1.5 L) and NaHCO3 powder. The
resulting mixture was filtered through a pad of Celite,
and the filtrate was extracted with CHCl3 (10 L). The
organic layer was washed with brine, dried over
Na2SO4, and concentrated. The residue was crystallized
from hexane–EtOAc (2:1) to give 17 as a colorless solid
(276 g, 75% yield). mp: 169–170 ꢁC; H NMR(CDCl )
1
3
d 0.82 (s, 9H), 3.74 (s, 3H), 3.98 (t, J=7.8 Hz, 1H), 4.67
(d, J=7.8 Hz, 1H), 5.11 (d, J=7.8 Hz, 1H), 5.12 (s,
2H), 5.91 (d, J=1.4 Hz, 1H), 5.93 (d, J=1.4 Hz, 1H),
6.46–6.50 (m, 2H), 6.77 (d, J=8.5 Hz, 1H), 6.86–6.88
(m, 2H), 7.12–7.17 (m, 1H), 7.32–7.54 (m, 7H), 8.49–
8.52 (m, 1H); The NOEs were observed between d 3.98
(Ha) and d 4.67 (Hb), d 3.98 (Ha) and d 5.11 (Hc), d
4.67 (Hb) and d 5.11 (Hc), d 4.67 (Hb) and d 6.87 (Hd),
d 4.67 (Hb) and d 6.86 (He). MS m/z 552 (M+H)+.
Anal. calcd for C34H33NO6: C, 74.03; H, 6.03; N, 2.54.
Found: C, 74.40; H, 6.18; N, 2.57.
(5RS,6SR,7SR)-6-tert-butoxycarbonyl-7-(2-Hydroxy-4-
methoxyphenyl)-5-(3,4-methylenedioxyphenyl)cyclopenteno
[1,2-b]pyridine (4). To a suspension of 19 (345 g, 625
mmol) in THF (2.0 L) and MeOH (2.0 L) was added
10% Pd/C (50 wt% H2O, 345 g), and the mixture was
hydrogenated at 3 atm of pressure at room temperature
overnight. The mixture was filtered through a pad of
Celite, washed with THF, and the filtrate was con-
centrated. The residue was crystallized from EtOAc–
hexane, and the crystalline solid was collected by filtra-
tion, and dried in vacuo at 40 ꢁC to give 4 as a pale
brown solid (258 g, 89% yield). mp: 167–168 ꢁC; 1H
NMR(CDCl 3); d 1.39 (s, 9H), 3.55 (dd, J=9.8, 10.2 Hz,
1H), 3.77 (s, 3H), 4.56 (d, J=9.8 Hz, 1H), 5.02 (d,
J=10.2 Hz, 1H), 5.97 (s, 2H), 6.44 (dd, J=2.6, 8.6 Hz,
1H), 6.61 (d, J=2.6 Hz, 1H), 6.66 (d, J=1.7 Hz, 1H), 6.72
(dd, J=1.7, 7.9 Hz, 1H), 6.80 (d, J=7.9 Hz, 1H), 7.04 (d,
J=8.6 Hz, 1H), 7.16 (dd, J=5.0, 7.7 Hz, 1H), 7.35 (dd,
J=1.4, 7.7 Hz, 1H), 8.37 (dd, J=5.0, 7.7 Hz, 1H); MS
+
.
m/z 462 (M+H) . Anal. calcd for C27H27NO6 0.2 hex-
ane: C, 70.75; H, 6.27; N, 2.93. Found: C, 70.97; H,
5.95; N, 3.12.
(5RS,6SR,7SR)-7-(2-Benzyloxy-4-methoxyphenyl)-6-tert-
butoxycarbonyl-5-(3,4-methylenedioxyphenyl)cyclopenteno-
[1,2-b]pyridine (19). To a solution of 17 (540 g, 979
mmol) in dioxane (2.5 L) and tert-BuOH (2.5 L) was
added tert-BuOK (11.0 g, 98.0 mmol), and the mixture
was stirred at 60 ꢁC for 1 h. After cooling to room tem-
perature, the mixture was partitioned between EtOAc
(2.5 L) and H2O (2.5 L). The organic layer was washed
with brine, dried over Na2SO4, and concentrated. The
residue was crystallized from hexane–EtꢁOAc (4:1) to
6-tert-Butoxycarbonyl-5-hydroxy-7-(2-hydroxy-4-methoxy-
phenyl)-5-(3,4-methylenedioxyphenyl)cyclopenteno[1,2-b]-
pyridine (20). To a solution of 15 (1.00 g, 1.77 mmol) in
THF (20 mL) and MeOH (20 mL) was added 10% Pd
on carbon (300 mg), and the mixture was hydrogenated
at atmospheric pressure at room temperature overnight.
The mixture was filtered through a pad of Celite, and
the filtrate was concentrated. The residue was purified
by column chromatography on silica gel to give 20 as a
pale yellow solid (697 mg, 83% yield). 1H NMR
(CDCl3); d 0.88 (s, 9H), 3.74 (s, 3H), 3.90 (d, J=6.3 Hz,
1H), 5.34 (d, J=6.3 Hz, 1H), 5.97 (s, 2H), 6.35 (dd,
J=2.7, 8.6 Hz, 1H), 6.46 (d, J=2.7 Hz, 1H), 6.80 (d,
J=8.2 Hz, 1H), 7.00 (dd, J=1.8, 8.2 Hz, 1H), 7.04 (d,
J=1.8 Hz, 1H), 7.06 (d, J=8.6 Hz, 1H), 7.29 (m, 1H),
7.68 (dd, J=1.5, 7.6 Hz, 1H), 8.51 (dd, J=1.5, 5.1 Hz,
1H); MS m/z 478 (M+H)+.
1
give 19 (501 g, 93% yield). mp: 160–161 C; H NMR
(CDCl3) 1.30 (s, 9H), 3.47 (t, J=10.5 Hz, 1H), 3.80 (s,
3H), 4.42 (d, J=10.5 Hz, 1H), 4.62 (d, J=10.5 Hz, 1H),
4.79 (d, J=10.6 Hz, 1H), 4.85 (d, J=10.6 Hz, 1H), 5.90
(s, 2H), 6.22 (dd, J=1.7, 8.0 Hz, 1H), 6.29 (d, J=1.7
Hz, 1H), 6.51 (d, J=7.9 Hz, 1H), 6.52 (dd, J=2.4, 7.9
Hz, 1H), 6.56 (d, J=2.4 Hz, 1H), 6.82–6.88 (m, 2H),
7.09–7.11 (m, 2H), 7.16–7.26 (m, 4H), 8.45–8.48 (m,
1H); The NOEs were observed between d 3.47 (Ha) and
d 6.22 (Hd), d 3.47 (Ha) and d 6.29 (He), d 4.42 (Hb)
and d 4.62 (Hc), d 4.42 (Hb) and d 6.22 (Hd), d 4.42
Acknowledgements
(Hb) and d 6.29 (He), d 4.62(Hc) and d 7.19 (Hf) . MS
We are grateful to Ms. Regina Stamatis, Merck & Co.,
Inc., for her critical reading of this manuscript. We also
thank Dr. Shigeru Nakajima for NOE experiments and
Ms. Chihiro Sato for analytical support.
+
.
m/z 552 (M+H) . Anal. calcd for C34H33NO6 0.3 hex-
ane: C, 74.46; H, 6.49; N, 2.42. Found: C, 74.69; H,
6.19; N, 2.54.

3444
K. Niiyama et al. / Bioorg. Med. Chem. 10 (2002) 3437–3444
6. In order to identify each structure of the product 7 and 8,
References and Notes
they were converted to the corresponding methyl ester 9 and
10 and separated by column chromatography on silica gel to
determine the ratio of the isomers via the reaction.
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