A facile access to spiro furanone skeleton based on Pd(II)-mediated cyclization-carbonylation of propargylic esters

Article abstract of DOI:10.1016/j.tet.2005.12.033

The oxidative cyclization-carbonylation of propargylic esters mediated by Pd(II) afforded cyclic orthoesters, which were hydrolyzed into γ-acetoxy-β-ketoesters. Based on the NMR experiments, it was presumed that the cyclization reaction was initiated by a

Full text of DOI:10.1016/j.tet.2005.12.033

Tetrahedron 62 (2006) 2545–2554
A facile access to spiro furanone skeleton based on
Pd(II)-mediated cyclization–carbonylation of propargylic esters
a
a
a
a
Keisuke Kato,a, Hideaki Nouchi, Keisuke Ishikura, Satoshi Takaishi, Satoshi Motodate,
*
Hikaru Tanaka,a Kazuho Okudaira,a Tomoyuki Mochida,b Ryuichiro Nishigaki,a
Koki Shigenobua and Hiroyuki Akitaa,
*
aFaculty of Pharmaceutical Sciences, Toho University, 2-2-1 Miyama, Funabashi, Chiba 274-8510, Japan
bDepartment of Chemistry, Faculty of Science, Toho University, 2-2-1 Miyama, Funabashi, Chiba 274-8510, Japan
Received 2 December 2005; revised 15 December 2005; accepted 16 December 2005
Available online 18 January 2006
Abstract—The oxidative cyclization–carbonylation of propargylic esters mediated by Pd(II) afforded cyclic orthoesters, which were
hydrolyzed into g-acetoxy-b-ketoesters. Based on the NMR experiments, it was presumed that the cyclization reaction was initiated by a
nucleophilic attack of carbonyl oxygen to the alkyne carbon coordinated to palladium(II). When the g-acetoxy-b-ketoesters were treated with
a basic condition, Knoevenagel–Claisen type condensation took place, and spiro furanone derivatives were obtained in good yields. We
applied these reactions to steroid derivatives, and steroid derivatives having a spiro furanone fragment were synthesized. Among them, the
spiro furanone 4j had vasorelaxant and bradycardiac activities. Compounds 2i–4k had inhibitory effect on CYP3A.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
of a spiro furanone skeleton by using Knoevenagel–Claisen
type condensation of g-acetoxy-b-ketoesters (Scheme 1).
Palladium(II)-catalyzed reactions are fundamentally
important in organic transformations.1 Propargylic esters
undergo a number of palladium catalyzed transformations,2
such as nucleophilic substitution,3 oxidative rearrangement4
and carbonylation reactions.5 Recently, we have reported
cyclization–carbonylation of 4-yne-1-ols,6 4-yne-1-ones7
and propargylic esters.8 These reactions are considered to be
a useful method for the conversion of the acetylene unit to a
b-ketoester unit.9 We would like to report here mechanistic
insight into the Pd(II)-mediated cyclization–carbonylation
of propargylic esters and an application to the construction
2. Results and discussion
2.1. Cyclization–carbonylation of propargylic esters
The cyclization–carbonylation of propargylic acetate 1a–d
in the presence of (CH3CN)2PdCl2/p-benzoquinone in
methanol at 0 8C–rt under carbon monoxide atmosphere
(balloon) afforded methoxycarbonylated orthoesters 2a–d in
61–71% yields (Scheme 2, Table 1, entries 1–4). In the case
R3
CO2Me
R2
R2 R3
R2
R3
R2 R3
(CH3CN)2PdCl2 (5 mol%)
p-benzoquinone (1.1 equiv)
O
H+
Base
O
O
O
O
O
O
R1
CO2Me
R1
R1
MeOH, CO balloon
R1
O
O
OMe
1
CO2Me
4
2
3
acetylene unit
β-ketoester unit
Scheme 1.
Keywords: Palladium; Orthoester; Cyclization–carbonylation; Propargylic ester; b-Ketoesters; Spiro furanone; 3(2H)-Furanone; Ethisterone; Mestranol;
Ethynylestradiol.
*
Corresponding authors. Tel./fax: C81 474 72 1825; e-mail: kkk@phar.toho-u.ac.jp
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.12.033

2546
K. Kato et al. / Tetrahedron 62 (2006) 2545–2554
R2
R3
CO2Me
R3
R2
R2 R3
(CH3CN)2PdCl2 (5 mol%)
O
p-benzoquinone (1.1 equiv)
O
O
O
O
CO2Me
R1
R1
2a–e, g
p-MeOPh
O
3f
O
MeOH, CO balloon
1a–g
OMe
Scheme 2.
Table 1. The cyclization–alkoxycarbonylation of propargylic esters
Entry
1
Condition
R1
R2
R3
Product
Yield (%)
1
2
3
4
5
6
7
1a
1b
1c
1d
1e
1f
0 8C, 7 h
0 8C, 3 h
0 8C, 5 h
rt, 0.5 h
0 8C, 4.5 h
rt, 1 h
Me
Me
Me
Me
Ph
p-MeOPh
p-NO2Ph
–(CH2)6–
–(CH2)5–
–(CH2)2NBoc(CH2)2–
CH2CH2Ph
–(CH2)5–
2a
2b
2c
2da
2e
3f
65
65
71
61
80
83
21
Me
–(CH2)5–
–(CH2)5–
1g
rt, 1 h
2g
a The product 2d was obtained as a 2:1 diastereomeric mixture.
of benzoates 1e–g, electronic effect of the p-substituents on
the phenyl group was observed. When benzoate 1e and
p-methoxy derivative 1f bearing an electron-donating group
were subjected to similar reaction conditions, the yields of
the products 2e and 3f were improved in comparison with
acetate 1a (entries 5 and 6). However, the reaction of
p-nitrobenzoate 1g having an electron-withdrawing group
scarcely proceeded and 2g was obtained in 21% yield
together with recovery of the substrate (65%) (entry 7). In
addition, in the case of a phenylacetylene derivative of 1b
and a TBDMS ether derivative of 1d, the reactions did not
proceed under similar reaction conditions. These results
suggested that the presence of neighboring group partici-
pation and nucleophilicity of the carbonyl oxygen play an
important role for initiating the reaction. The substrate 1h
bearing two phenyl groups in propargylic position afforded
different products 510 (36%) and 6 (23%) from those of
Table 1 (Fig. 1). These products 5 and 6 should be produced
by SN1-type substitution of the acetoxy group with MeOH
and by oxidative rearrangement of propargylic acetate,4
respectively.
Two kinds of mechanistic pathways have been proposed for
the intramolecular cyclization of alkynes with a C]O
group. Yamamoto et al. reported the cyclization of alkynyl
aldehydes takes place via a hemiacetal intermediate based
on NMR experiment,11 and then we have also reported the
asymmetric cyclization–carbonylation of 2-alkynyl-1,3-
diketone proceeded through a similar pathway.12 On the
other hand, in the case of alkynyl ketones and propargylic
esters, we have proposed an alternative pathway.7,8 The
reaction could be initiated by a nucleophlic attack of the
C]O group to the triple bond coordinated to palladium(II)
followed by orthoester formation. Recently, Bacchi et al.
have reported oxidative cyclization–alkoxycarbonylation of
prop-2-ynyl a-ketoesters afforded the products, resulting
from MeOH attack on the ester carbonyl group followed by
cyclization and carbonylation.5a Thus, to clarify the
mechanism of the Pd(II)-mediated cyclization of pro-
pargylic esters, NMR studies of a 1:1 mixture of 1b and
(CH3CN)2PdCl2 in CD2Cl2 at rt were carried out according
1
to the precedent.11 The H and 13C NMR spectra clearly
showed the disappearance of acetylenic proton (d 2.61) and
carbons (d 84.2, 74.3), newly generated proton (d 5.46) and
carbons appeared. The three secondary carbon signals (d
37.3, 25.5, 22.8) split into five secondary carbon resonances
(d 34.9, 31.8, 30.0, 27.3, 26.5), which suggest that the
symmetry of the cyclohexane moiety was lost. To our
regret, the mixtures became black after 30 min. We
tentatively proposed the above mixtures to be vinyl
palladium complex A such as shown in Figure 3.13,14
Although the structure of the above mixtures could not be
clarified,15 it is possible that the reaction is initiated by a
nucleophilic attack of the carbonyl oxygen to the triple bond
coordinated with palladium(II).
Ph
Ph
Ph
Ph
O
O
1h
OMe
5
Me
Ph
Ph
OAc
OMe
6
OMe
Figure 1.
Selected data of the NMR spectra measured in CD3-
COCD3 of 2b are shown in Figure 2. The quaternary
carbon of orthoester appeared in 124 ppm and its HMBC
correlations with proton of the methyl group (1.6 ppm)
and with proton of the methoxy group (3.24 ppm) were
clearly observed. These results indicated the presence of
an orthoester structure. In addition, the structure of 2c
was unequivocally determined by X-ray crystallographic
analysis.
A plausible mechanism of the present reactions would be
proposed as shown in Scheme 3. Propargylic acetate 1 reacts
with Pd(II) to generate vinyl palladium intermediate B,
which was subjected to the nucleophilic attack of MeOH on
the carbon atom of the carbonyl group followed by CO
insertion to provide the orthoester products 2. In the case of
benzoate 1e and p-methoxybenzoate 1f, the cationic
intermediate B (R3ZPh and p-MeO–Ph) should be
stabilized by an electron-donating group, and

K. Kato et al. / Tetrahedron 62 (2006) 2545–2554
2547
2.2. Synthesis of spiro furanones
: HMBC correlations
O
13
1.60
ppm
H C
3
: Chemical shift of C NMR
3(2H)-Furanones are of pharmacological significance and
represent important building blocks for natural product
synthesis.16 A number of syntheses17 and biological
activities, such as selective inhibitory activity on COX-2
(cyclooxygenase-2),18 inhibitory activity on MAO (mono-
amine oxidase),19 anti-cataract effect on spontaneous
cataract rats,20 cytotoxic activity against human tumor
cell21 and antiallergic activity22 have been reported. As an
application of the above cyclization–carbonylation reaction,
the facile synthesis of 3(2H)-furanones have been achieved
(Scheme 4, Table 2). The cyclic orthoesters 2 were
converted to the corresponding g-acetoxy-b-ketoesters 3
by acid treatment in good yields. When g-acetoxy-b-
ketoesters 3 were treated with a base, Knoevenagel–Claisen
type condensation took place, furanones 4 were obtained in
good yields. In some cases (3c and 3d), though the use of
K2CO3 leads to decrease in yield, it has been improved by
using NaHCO3.
CO CH
2
3
1
: Chemical shift of H NMR
O
3.24
ppm
H CO
3
2b
124 ppm
Figure 2. Selected data of 1H, 13C NMR and HMBC spectra of 2b.
O
PdCl(CH3CN)2
H
Me
Cl
O
A
Figure 3. Proposed vinyl palladium complexes A.
R1
OH
O
O
R2
R3
Pd2+
OH
2H+
Substrate 1
O
O
R1
O
O
R2
O
H+
+
2CO2Me
2.3. Synthesis of steroid derivatives containing spiro
furanone fragment
Pd2+
Pd(0)
R3
R
1R
O
R3
MeO
R1
R
O
Next, we applied these reaction sequences to steroid
derivatives, acetates of ethisterone, mestranol and ethynyles-
tradiol. The cyclization–carbonylation of propargylic acetate
1i and 1j in the presence of (CH3CN)2PdCl2/p-benzoquinone
in methanol at 0 8C under carbon monoxide atmosphere
(balloon) afforded the corresponding orthoesters 2i and 2j in
100 and 86% yields, respectively (Scheme 5, Table 3). In the
case of diacetate 1k, partial deacetylation was observed, 2k
was obtained in 30% yield together with acetate 2l (43%
yield). Treatment of 2i–2k with 10% HCl in MeOH gave the
corresponding b-ketoesters 3i–3k in 88–98% yields. The spiro
furanones 4i–4k were obtained by treatment of 3i–3k under
basic conditions in 92–99% yields.
H
2Pd+
H
R
MeOH
1R2
Product 2
COPd+
H
R3
O
intermediate B
R3
MeO
O
+
O
MeOH
3f
R
1R2
Pd+
H
O
R3
MeO
CO
H+
O
Scheme 3.
nucleophilicity of the carbonyl oxygen should be increased.
Therefore, the yield of the products could be improved.
While the electron-withdrawing effect of the nitro group
caused decreased nucleophilicity of the carbonyl oxygen in
1g, the reaction scarcely proceeded. In the case of
p-methoxybenzoate 1f, the orthoester bond of 2f (R3Z
p-MeO–Ph) should be easily cleaved, to afford b-ketoester
3f directly.
2.4. Biological activity
Steroid compounds in general are known for their effects on
various receptors, ion channels and enzymes. In the present
R2 R3
R2
R3
R2
R3
Method A : K2CO3, MeOH
or
O
O
CO2Me
10% HCl, MeOH
rt, 10 min~3 h
O
O
O
R1
MeO
CO2Me
R1
O
R1
O
Method B : NaHCO3, MeOH
2
CO2Me
4
3
Scheme 4.
Table 2. The conversion of orthoesters 2 into furanones 4
Entry
2
R1
R2
R3
Product 3 (yield %)
Condition (method
A or B)
Product 4 (yield %)
1
2
3
2a
2b
2c
Me
Me
Me
–(CH2)6–
–(CH2)5–
–(CH2)2NBoc(CH2)2–
3a (98)
3b (96)
3c (quant.)
rt 3 h (A)
rt 3 h (A)
rt 1.5 h (A)
rt 24 h (B)
rt 3 h (A)
rt 24 h (B)
rt 48 h (B)
4a (quant.)
4b (96)
4c (57)
4c (96)
4d (28)
4d (89)
4e (84)
4
5
2d
2e
Me
Ph
Me
PhCH2CH2
3d (83)
3e (91)
–(CH2)5–

2548
K. Kato et al. / Tetrahedron 62 (2006) 2545–2554
CH3
CO2Me
CH3
OAc
CO2Me
CH3
CH3
1i
O
O
OCH3
CH3
O
CH3O2C
O
O
O
O
Condition (1)
Condition (2)
Condition (3)
O
CH3
OAc
4i, 4j (R = Me),
4k (R = H)
3i, 3j (R = Me),
3k (R = H)
2i, 2j (R = Me),
2k (R = H), 2l (R = Ac)
Condition (1) : (C H3CN)2PdCl2 (5 mol%), p-benzoquinone (1.6 equiv), CO, MeOH
Condition (2) : 10% HCl / MeOH
1j (R = Me)
1k (R = Ac)
RO
Condition (3) : Method A : K2CO3/MeOH, Method B : NaHCO3/MeOH
Scheme 5.
Table 3. The reaction of 17-alkynylsteroid derivatives 1i–1k
Entry
1
Condition (1) Product 2 (yield %)
Condition (2) Product 3 (yield %)
Condition (3)
Product 4 (yield %)
1
2
3
1i
1j
1k
0 8C, 15 h
0 8C, 72 h
0 8C, 24 h
2i (quant.)
2j (86)
2k (30) (RZH) and 2l (43) rt, 1 h
(RZAc)
rt, 0.5 h
rt, 3 h
3i (88)
3j (98)
3k (95 from 2k)
Method A, rt, 1 h
Method B, rt, 24 h
Method B, rt, 24 h
4i (92)
4j (99)
4k (94 from 3k)
study, we examined the effects of synthesized compounds
2i–4k on isolated cardiovascular preparations and on
CYP3A activity.
beats per minute. The test compounds (10K5 M) slightly
affected the beating rate. The change in beating rate was
expressed as a percentage of the basal beating rate and
summarized (Table 4). Among them, the spiro furanone 4j
had vasorelaxant and bradycardiac activities.
(1) Cardiovascular effect: in aortic rings precontracted with
10K5 M norepinephrine, test compounds (10K5 M), showed
endothelium-independent relaxant effects. The relaxation
was expressed as a percentage of the maximum relaxation
by 10K4 M papaverine and summarized (Table 4). The
spontaneous beating rate of isolated right atria was 193–200
(2) Inhibitory effect on CYP 3A activity: test compounds
2i–4k have inhibitory effect on CYP3A activity assessed
by midazolam 10-hydroxylation. Preincubated with 3!
10K5 M of the test compounds, the activity of rat hepatic
microsomes was decreased to 40–90% of control values
(Table 5). Some steroid compounds such as 17a-
ethynylestradiol and danazol containing a terminal
acetylene moiety on the C17 position have been known
to decrease CYP3A activity and cause drug–drug
interactions in the clinical situation. Though compounds
2i–4k do not contain the terminal acetylene moiety, they
also have inhibitory effect on CYP3A. These results
might be a clue to clarifying the mechanism of the
inhibition.
Table 4. Cardiovascular effects of test compounds
Compound no.
Relaxation (%)
Changes in heart rate
(%)
2i
3i
4i
2j
9.0G1.4
5.4G2.6
4.2G2.3
10.0G3.7
9.5G1.6
18.7G3.4
7.9G2.2
1.3G1.0
13.0G1.9
3.1G0.5
29.2G5.8
1.2G1.1
1.0G3.0
K1.3G1.1
2.9G2.6
K1.7G7.2
K11.4G1.8
K2.7G3.9
3.9G1.9
0.4G3.2
5.7G5.1
K0.03G5.3
3j
4j
4k
2l
2k
2a
Estradiol
3. Conclusion
We have reported Pd(II)-mediated cyclization–carbony-
lation of propargylic esters. This reaction is considered to
be a useful method for the conversion of the acetylene
unit to a g-acetoxy-b-ketoester unit. Based on the NMR
experiments, it was presumed that the cyclization
reaction was initiated by a nucleophilic attack of
carbonyl oxygen to the alkyne carbon coordinated to
palladium(II). As an application of this reaction, we have
developed a new method for the construction of a spiro
furanone skeleton, and steroid derivatives having a spiro
furanone fragment were synthesized. Among them, the
spiro furanone 4j had vasorelaxant and bradycardiac
activities. Compounds 2i–4k had inhibitory effect on
CYP3A.
Values are the meanGstandard error of the mean from 3 to 5 preparations.
Table 5. Effect of test compounds 2i–4k on midazolam hydroxylation
Compound no.
Activity
2i
3i
4i
2j
3j
4j
4k
2l
2k
63.8G2.5
69.8G13.9
92.2G2.8
45.2G10.4
47.3G3.2
57.1G3.5
61.5G5.6
60.8G6.5
44.9G5.4
Values are the meanGstandard deviation of three experiments.

K. Kato et al. / Tetrahedron 62 (2006) 2545–2554
2549
4. Experimental
(OMe of orthoester), 51.1 (OMe of ester), 88.1 (quaternary,
O–C), 90.2 (OC]CH), 124.3 (quaternary, orthoester),
167.1 (CO of ester), 176.7 (OC]CH); EI-MS m/z: 270
(MC); IR (KBr) 2932, 1714, 1642, 1141, 1044 cmK1. Anal.
Found: C, 61.88; H, 8.29 Calcd for C14H22O5: C, 62.20; H,
8.20%.
4.1. General experimental methods
All melting points were measured on a Yanaco MP-3S
micro melting point apparatus and are uncorrected. 1H, 13
C
NMR and HMBC spectra were recorded on JEOL AL 400
and JEOL Lambda 500 spectrometer in CDCl3 with Me4Si
as an internal reference. In the case of acetone-d6, solvent
peak were used as a reference (2.04 ppm for 1H and
29.8 ppm for 13C). High-resolution mass spectra (HR-MS)
and the fast atom bombardment mass spectra (FAB MS)
were obtained with a JEOL GC mate II and a JEOL JMS 600
H spectrometer, respectively. IR spectra were recorded with
a JASCO FT/IR-300 spectrometer. All reagents were
purchased from commercial sources and used without
purification. All evaporations were performed under
reduced pressure. For column chromatography, silica-gel
(Kieselgel 60) was employed.
4.3.2.
Methyl
(2E)-(2-methoxy-2-methyl-1,3-
dioxaspiro[4.5]dec-4-ylidene)acetate 2b. Hexane/ethyl
acetateZ50:1. Colorless oil. 1H NMR (CD3COCD3) d
1.33–1.41 (1H, m), 1.60 (3H, s), 1.56–1.70 (6H, m), 1.75–
1.81 (1H, m), 2.48–2.57 (1H, m), 2.61–2.69 (1H, m), 3.24
(3H, s, OMe of orthoester), 3.61 (3H, s, OMe), 5.27 (1H, s);
13C NMR (CD3COCD3) d 22.5, 22.7, 25.2, 25.2, 32.1, 33.2,
49.7 (OMe of orthoester), 51.1 (OMe of ester), 87.4
(quaternary, O–C), 89.2 (OC]CH), 124.1 (quaternary,
orthoester), 167.0 (CO of ester), 171.6 (OC]CH); EI-MS
m/z: 256 (MC); IR (KBr) 2862, 1716, 1649, 1075, 1052,
977 cmK1. Anal. Found: C, 61.22; H, 8.12 Calcd for
C13H20O5: C, 60.92; H, 7.87%.
4.2. Preparation of substrates
4.3.3.
tert-Butyl
(4E)-2-methoxy-4-(2-methoxy-
The substrates 1 were prepared by acetylation (Ac2O/
pyridine) of the corresponding alcohols. The acetates 1
except 1f were known compounds.23
2-oxoethylidene)-2-methyl-1,3-dioxa-8-azaspiro[4.5]-
decane-8-carboxylate 2c. Hexane/ethyl acetateZ30:1.
Colorless needles. Mp 78 8C (hexane); 1H NMR (CD3-
COCD3) d 1.46 (9H, s), 1.58–1.64 (1H, m), 1.65 (3H, s),
1.73–1.79 (1H, m), 2.67–2.85 (2H, m), 2.94–3.10 (2H, m),
3.27 (3H, s), 3.61 (3H, s), 4.01–4.12 (2H, m), 5.34 (1H, s);
13C NMR (CD3COCD3) d 24.8, 28.6, 31.9, 32.9, 40.5 (br),
41.2 (br), 49.9, 51.2, 79.4, 85.4, 89.9, 124.1, 154.8, 166.6,
172.5; FAB-MS m/z: 380 (MCCNa); IR (KBr) 1690, 1652,
1135, 1077, 1045 cmK1. Anal. Found: C, 57.27; H, 7.47
Calcd for C17H27NO7: C, 57.13; H, 7.61%.
4.2.1. 1-Ethynyl-1-cyclohexyl 4-methoxybenzoate 1f.
Colorless oil. 1H NMR (CDCl3) d 1.37–1.57 (2H, m),
1.63–1.75 (4H, m), 2.05–2.24 (4H, m), 2.64 (1H, s), 3.84
(3H, s), 6.90 (2H, d, JZ6.8 Hz), 7.99 (2H, d, JZ6.8 Hz);
13C NMR (CDCl3) d 22.4 (2C), 25.2, 37.1 (2C), 55.4, 74.2,
75.1, 84.0, 113.5 (2C), 123.4, 131.6 (2C), 163.3, 164.4;
HRMS-EI m/z: [MC] calcd for C16H18O3 258.1256; found
258.1246; IR (KBr) 2937, 1719, 1606, 1253 cmK1. Anal.
Found: C, 73.95; H, 7.02 Calcd for C16H18O3: C, 74.39; H,
7.02%.
4.3.3.1. X-ray crystallographic analysis. X-ray diffrac-
tion data for 2c were collected on a Bruker SMART APEX
CCD diffractometer equipped with a graphite crystal and
4.3. General procedure for the cyclization–carbony-
lation of propargylic esters 1a–1h
A 30 mL two-necked round-bottomed flask, containing a
magnetic stirring bar, (CH3CN)2PdCl2 (0.05 mmol),
p-benzoquinone (1.1 mmol) and MeOH (6 mL) was fitted
with a rubber septum and three-way stopcock connected to a
balloon filled with carbon monoxide. The apparatus was
purged with carbon monoxide by pumping–filling via the
three-way stopcock. A solution of the substrate 1 (1 mmol)
in MeOH (3 mL) was added dropwise to the stirred mixture
via a syringe at 0 8C. After being stirred for the appropriate
period of time, the mixture was diluted with CH2Cl2
(30 mL), washed with 5% NaOH aq (40 mL), and dried over
MgSO4. The solution was concentrated under reduced
pressure. The crude product was purified by column
chromatography on silica-gel. The fraction eluted with
hexane–ethyl acetate (100/1–30/1) afforded 2 or 3f.
Figure 4.
4.3.1. Methyl (2E)-(2-methoxy-2-methyl-1,3-dioxas-
piro[4.6]undec-4-ylidene)acetate 2a. Hexane/ethyl acet-
ateZ50:1. Colorless needles. Mp 42 8C (MeOH); 1H NMR
(CD3COCD3) d 1.58–1.82 (9H, m), 1.60 (3H, s), 1.90–1.97
(1H, m), 2.53–2.60 (1H, m), 2.67–2.76 (1H, m), 3.24 (3H, s,
orthoester), 3.61 (3H, s, ester), 5.21 (1H, s); 13C NMR
(CD3COCD3) d 3.2, 23.2, 25.4, 27.9, 27.9, 36.4, 37.6, 49.6
incident beam monochromator using Mo Ka radiation (lZ
˚
0.71073 A). The structures were solved by the direct method
(SHELXS 9724) and expanded using Fourier techniques.
The non-hydrogen atoms were refined anisotropically. The
crystal contains two crystallographically independent
molecules, one of which exhibits disorder with respect to

2550
K. Kato et al. / Tetrahedron 62 (2006) 2545–2554
the methyl and methoxy substituents attached to the five-
membered ring. An ORTEP25 diagram of the disorder-free
molecule is shown in Figure 4. Crystallographic parameters:
32.3, 32.4, 50.7, 51.4, 88.6, 90.8, 121.9, 124.4, 128.0, 145.5,
149.6, 166.8, 173.4; HRMS-FAB m/z: [MCCH] calcd for
C18H22NO7 364.1396; found 364.1385; IR (KBr) 2934,
1716, 1655, 1528, 1354, 1134 cmK1. Anal. Found: C, 57.65;
H, 5.82; N, 3.41 Calcd for C18H21NO71/2H2O: C, 58.06; H,
5.96%; N, 3.76.
ꢀ
C17H27NO7, MWZ357.40, triclinic, space group P1, with
˚
˚
unit cell aZ10.4863(7) A, bZ12.5804(8) A, cZ
˚
15.345(1) A, aZ74.778(1)8, bZ74.247(1)8, gZ
3
˚
79.900(1)8, and VZ1868.2(2) A . ZZ4, Dcalcd
Z
1.271 g cmK3, TZ173 K, l(Mo Ka)Z0.71073 A. R1(IO
2s(I))Z0.0574, wR2Z0.1602, R1(all data)Z0.0730,
wR2Z0.1732, 9154 independent reflections (R(int)Z
0.0154), 488 parameters refined on F2. Crystallographic
data have been deposited with the Cambridge Crystallo-
graphic Data Centre.
4.3.8. 1,10-(1-Methoxy-2-propynylidene)bisbenzene 5.
Hexane/ethyl acetateZ50:1. Colorless oil. Spectral data
was identical with that of literature’s.10
˚
4.3.9. 3,3-Dimethoxy-1,1-diphenyl-1-propen-2-ol acetate
6. Hexane/ethyl acetateZ50:1. Colorless needles. Mp 74 8C
1
(hexane); H NMR (CDCl3) d 1.97 (3H, s), 3.36 (6H, s),
4.3.4. Methy (2E)-[2-methoxy-2,5-dimethyl-5-(phenyl-
ethyl)-1,3-dioxolan-4-ylidene]acetate 2d. Hexane/ethyl
acetateZ50:1. Colorless oil. Mixture of two diastereomers
(ratioZ2:1). 1H NMR (CD3COCD3) (major diastereomer) d
1.69 (3H, s), 1.77 (3H, s), 2.25–2.51 (2H, m), 2.55–2.77
(2H, m), 3.31 (3H, s), 3.62 (3H, s), 5.37 (1H, s), 7.13–7.28
(5H, m); (minor diastereomer) d 1.65 (3H, s), 1.73 (3H, s),
3.35 (3H, s), 3.61 (3H, s), 5.32 (1H, s); 13C NMR
(CD3COCD3) (major diastereomer) d 22.9, 23.7, 30.9,
40.0, 50.5, 51.2, 88.1, 89.9, 124.0, 126.6, 129.2, 129.2,
142.7, 167.1, 174.1; EI-MS m/z: 275 (MCKOMe); IR
(KBr) 2946, 1715, 1652, 1142, 1104, 1055 cmK1. Anal.
Found: C, 66.52; H, 7.32 Calcd for C17H22O5: C, 66.65; H,
7.24%.
4.77 (1H, s), 7.20–7.40 (10H, m); 13C NMR (CDCl3) d 20.8,
54.9, 101.1, 127.6, 127.9, 128.1, 128.3, 129.8, 135.7, 138.1,
138.3, 140.7, 168.4; FAB-MS m/z: 281 (MCKMeO); IR
(KBr) 1764, 1193, 1074, 1228 cmK1. Anal. Found: C,
72.80; H, 6.44 Calcd for C19H20O4: C, 73.06; H, 6.45.
4.4. Preparation of g-hydroxy-b-ketoesters 3
A solution of the orthoester 2 (1 mmol) in MeOH (10 mL),
H2O (2 mL) and 10% HCl aq (1 mL) was stirred for the
appropriate period of time, the mixture was diluted with
EtOAc (30 mL) and H2O (30 mL). The organic layer was
dried over MgSO4. The solution was concentrated under
reduced pressure. The crude product was purified by column
chromatography on silica-gel. The fraction eluted with
hexane–ethyl acetate (10/1–4/1) afforded 3.
4.3.5.
dioxaspiro[4.5]dec-4-ylidene)acetate 2e. Hexane/ethyl
Methyl
(2E)-(2-methoxy-2-phenyl-1,3-
1
acetateZ100:1. Colorless oil. H NMR (CDCl3) d 1.40–
4.4.1. Methyl 3-(1-acetoxycycloheptyl)-3-oxopropanoate
3a. Hexane/ethyl acetateZ10:1. Colorless oil. 1H NMR
(CDCl3) d 1.59 (9H, br s), 1.94–2.10 (3H, m), 2.11 (3H, s),
3.48 (2H, s), 3.72 (3H, s); 13C NMR (CDCl3) d 21.1, 22.7,
29.4, 34.2, 42.7, 52.4, 89.2, 167.7, 170.5, 201.0; FAB-MS
1.50 (2H, m), 1.63–1.75 (5H, m), 1.91–1.94 (1H, m), 2.44
(1H, dt, JZ5.2, 13.2 Hz), 2.66–2.71 (1H, m), 3.32 (3H, s),
3.64 (3H, s), 5.43 (1H, s), 7.36–7.37 (3H, m), 7.55–7.58
(2H, m); 13C NMR (CDCl3) d 21.9, 22.1, 24.4, 31.7, 31.7,
50.5, 51.0, 87.6, 89.6, 122.1, 125.8, 128.3, 129.5, 137.6,
166.7, 173.5; FAB-MS m/z: 319 (MCCH); IR (KBr) 2934,
1715, 1652, 1135, 1043 cmK1. Anal. Found: C, 68.19; H,
6.82 Calcd for C18H22O5: C, 67.91; H, 6.97%.
m/z: 257 (MCCH); IR (KBr) 2931, 1737, 1247 cmK1
.
Anal. Found: C, 60.62; H, 7.82 Calcd for C13H20O5: C,
60.92; H, 7.87%.
4.4.2. Methyl 3-(1-acetoxycyclohexyl)-3-oxopropanoate
3b. Hexane/ethyl acetateZ10:1. Colorless oil. 1H NMR
(CDCl3) d 1.22–1.32 (1H, m), 1.47–1.61 (2H, m), 1.66–1.73
(5H, m), 2.02–2.06 (2H, m), 2.13 (3H, s), 3.50 (2H, s), 3.72
(3H, s); 13C NMR (CDCl3) d 20.9, 21.2, 24.9, 30.7, 42.8,
52.4, 85.2, 167.6, 170.4, 201.2; EI-MS m/z: 242 (MC); IR
(KBr) 2942, 1739, 1234 cmK1. Anal. Found: C, 59.28; H,
7.48 Calcd for C12H18O5: C, 59.49; H, 7.49%.
In the case of p-methoxybenzoate 1f, g-acetoxy-b-ketoester
3f was obtained directly.
4.3.6.
1-(3-Methoxy-1,3-dioxopropyl)cyclohexyl
4-methoxy-benzoate 3f. Hexane/ethyl acetateZ30:1.
Colorless oil. 1H NMR (CD3COCD3) d 1.29–1.38 (1H,
m), 1.58–1.81 (7H, m), 2.20–2.23 (2H, m), 3.59 (2H, s),
3.62 (3H, s), 3.90 (3H, s), 7.06 (2H, d, JZ8.8 Hz), 8.05 (2H,
d, JZ8.8 Hz); 13C NMR (CD3COCD3) d 22.1 (2C), 25.6,
31.4 (2C), 43.5, 52.2, 56.0, 85.8, 114.9 (2C), 122.7, 132.7
(2C), 165.0, 165.9, 168.2, 202.1; HRMS-FAB m/z: [MCC
H] calcd for C13H23O6 335.1495; found 335.1495; IR (KBr)
2939, 1752, 1707, 1605, 1255 cmK1. Anal. Found: C, 63.41;
H, 6.52 Calcd for C18H22O61/2H2O: C, 62.96; H, 6.75%.
4.4.3. Methyl 3-(4-acetoxy-1-tert-butoxycarbonylpiperi-
din-4-yl)-3-oxopropanoate 3c. Hexane/ethyl acetateZ4:1.
Colorless needles. Mp 99 8C (hexane); 1H NMR (CDCl3) d
1.46 (9H, s), 1.89–2.04 (4H, m), 2.15 (3H, s), 3.03–3.10
(2H, m), 3.51 (2H, s), 3.73 (3H, s), 3.89–4.02 (2H, m); 13C
NMR (CDCl3) d 20.8, 28.4, 30.4, 38.8 (br), 42.8, 52.5, 80.0,
83.0, 154.6, 167.3, 170.3, 199.9; FAB-MS m/z: 344
(MCCH); IR (KBr) 1754, 1682, 1273, 1228 cmK1. Anal.
Found: C, 55.91; H, 7.27; N, 3.83 Calcd for C16H25NO7: C,
55.97; H, 7.34; N, 4.08%.
4.3.7. Methyl (2E)-[2-methoxy-2-(4-nitrophenyl)-1,3-
dioxaspiro[4.5]dec-4-ylidene]acetate 2g. Hexane/ethyl
acetateZ70:1. Colorless oil. 1H NMR (CD3COCD3) d
1.39–1.42 (2H, m), 1.61–1.76 (5H, m), 1.93–1.97 (1H, m),
2.47 (1H, dt, JZ5.2, 13.2 Hz), 2.67–2.76 (1H, m), 3.39 (3H,
s), 3.64 (3H, s), 5.48 (1H, s), 7.85 (2H, d, JZ8.8 Hz), 8.31
(2H, d, JZ8.8 Hz); 13C NMR (CDCl3) d 22.5, 22.7, 25.1,
4.4.4. Methyl 4-acetyloxy-4-methyl-3-oxo-6-phenyl-
hexanoate 3d. Hexane/ethyl acetateZ10:1. Colorless oil.
1H NMR (CDCl3) d 1.60 (3H, s), 2.04–2.28 (2H, m), 2.06

K. Kato et al. / Tetrahedron 62 (2006) 2545–2554
2551
1
(3H, s), 2.56–2.67 (2H, m), 3.50 (1H, d, JZ15.6 Hz), 3.58
(1H, d, JZ15.6 Hz), 3.72 (3H, s), 7.14–7.21 (3H, m), 7.26–
7.30 (2H, m); 13C NMR (CDCl3) d 20.4, 21.0, 29.5, 37.7,
43.4, 52.4, 86.1, 126.2, 128.3, 128.5, 140.8, 167.4, 170.3,
201.0; FAB-MS m/z: 293 (MCCH); IR (KBr) 2951, 1741,
1249 cmK1. Anal. Found: C, 65.44; H, 6.88 Calcd for
C16H20O5: C, 65.74; H, 6.90%.
5:1. Colorless oil. H NMR (CDCl3) d 1.44 (3H, s), 2.04–
2.17 (2H, m), 2.53 (2H, t, JZ8.0 Hz), 2.60 (3H, s), 3.85
(3H, s), 7.12–7.28 (5H, m); 13C NMR (CDCl3) d 17.8, 22.1,
29.3, 38.1, 51.6, 92.4, 107.9, 126.2, 128.3, 128.5, 140.5,
163.3, 196.0, 199.8; HRMS-FAB m/z: [MCCH] calcd for
C16H19O4 275.1283; found 275.1285; IR (KBr) 2950, 1709,
1592, 1443, 1199 cmK1. Anal. Found: C, 69.6; H, 6.70
Calcd for C16H18O4: C, 70.06; H, 6.61%.
4.4.5. 1-(3-Methoxy-1,3-dioxopropyl)cyclohexyl benzoate
3e. Hexane/ethyl acetateZ50:1. Colorless oil. 1H NMR
(CD3COCD3) d 1.30–1.37 (1H, m), 1.58–1.85 (7H, m),
2.23–2.26 (2H, m), 3.57 (2H, s), 3.71 (3H, s), 7.47–7.51 (2H,
m), 7.58–7.64 (1H, m), 8.07–8.10 (2H, m); 13C NMR
(CD3COCD3) d 21.4 (2C), 25.0, 31.8 (2C), 42.8, 52.4, 85.7,
128.6, 129.4, 129.9, 133.7, 165.6, 167.7, 201.3; EI-MS m/z:
304 (MC); IR (KBr) 2940, 1752, 1717, 1292 cmK1. Anal.
Found: C, 67.12; H, 6.80 Calcd for C17H20O5: C, 67.09; H,
6.62%.
4.5.5. Methyl 4-oxo-2-phenyl-1-oxaspiro[4.5]dec-2-en-3-
carboxylate 4e. Hexane/ethyl acetateZ20:1. Colorless
needles. Mp 63 8C (hexane); H NMR (CDCl3) d 1.38–
1.47 (1H, m), 1.65–1.87 (9H, m), 3.83 (3H, s), 7.46–7.63
(3H, m), 7.91–7.94 (2H, m); 13C NMR (CDCl3) d 21.6 (2C),
24.4, 31.9 (2C), 51.9, 91.3, 106.8, 128.3, 129.3, 129.4,
133.1, 163.6, 187.3, 201.2; FAB-MS m/z: 287 (MCCH); IR
(KBr) 2947, 1702, 1604, 1567, 1387, 1089 cmK1. Anal.
Found: C, 71.28; H, 6.39 Calcd for C17H18O4: C, 71.31; H,
6.34%.
1
4.5. Preparation of furanones 4a–4e
4.6. Reaction of steroids
(Method A). A solution of the g-hydroxy-b-ketoester 3
(1 mmol) in MeOH (8 mL) and K2CO3 (138 mg, 1 mmol)
was stirred for the period of time, the mixture was diluted
with EtOAc (30 mL) and H2O (30 mL). The organic layer
was dried over MgSO4. The solution was concentrated
under reduced pressure. The crude product was purified by
column chromatography on silica-gel. The fraction eluted
with hexane–ethyl acetate (20/1–3/1) afforded 4.
The cyclization–carbonylation of propargylic esters 1i–1k
A 100 mL two-necked round-bottomed flask, containing a
magnetic stirring bar, (CH3CN)2PdCl2 (0.025 mmol), p-ben-
zoquinone (0.8 mmol) and MeOH (7 mL) was fitted with a
rubber septum and three-way stopcock connected to a balloon
filled with carbon monoxide. The apparatus was purged with
carbon monoxide by pumping–filling via the three-way
stopcock. A solution of the substrate 1 (0.5 mmol) in MeOH
(35 mL) was added dropwise to the stirred mixture via a
syringeat0 8C. Afterbeingstirredfor theappropriateperiodof
time at 0 8C, the mixture was diluted with CH2Cl2 (70 mL),
washed with 5% NaOH aq (50 mL), and dried over MgSO4.
The solution was concentrated under reduced pressure. The
crude product was purified by column chromatography on
silica-gel. The fraction eluted with hexane–ethyl acetate (30/
1–10/1) afforded 2.
(Method B). NaHCO3 (2 equiv) was used instead of K2CO3
(1 equiv).
4.5.1. Methyl 2-methyl-4-oxo-1-oxaspiro[4.6]undec-2-
en-3-carboxylate 4a. Hexane/ethyl acetateZ5:1. Colorless
oil. 1H NMR (CDCl3) d 1.61–1.76 (10H, m), 1.87–1.95 (2H,
m), 2.60 (3H, s), 3.83 (3H, s); 13C NMR (CDCl3) d 18.0,
22.3, 29.2, 35.2, 51.5, 95.0, 106.4, 163.7, 195.3, 201.2;
HRMS-EI m/z: [MC] calcd for C13H18O4 238.1205; found
238.1210; IR (KBr) 2929, 1710, 1594, 1441, 1205,
1146 cmK1
.
4.6.1. Steroidal spiro orthoester 2i. Hexane/ethyl acetateZ
10:1. Colorless needles. Mp 70 8C (MeOH); mixture of two
diastereomaers (ratioZ5:1). 1H NMR (CDCl3) (major
diastereomer) d 0.84–1.05 (2H, m), 0.98 (3H, s), 1.19 (3H,
s), 1.35–1.50 (3H, m), 1.59–1.74 (4H, m), 1.66 (3H, s), 1.91–
2.03(4H, m), 2.14–2.47 (5H, m), 2.85–2.93 (1H, m), 3.19(3H,
s), 3.65(3H, s), 5.62(1H,s), 5.73(1H,s);(minordiastereomer)
d 0.96, 1.19, 1.59, 3.38, 3.64 (s each, Me), 5.52, 5.73 (s each,
C]CH); 13C NMR (CDCl3) (major diastereomer) d 14.8,
17.3, 20.8, 24.5, 24.5, 31.8, 32.1, 32.8, 33.4, 33.9, 35.6, 36.6,
38.5, 48.8, 49.7, 50.5, 51.3, 53.2, 93.5, 98.1, 120.8, 123.9,
166.5, 169.9, 171.0, 199.4; HRMS-EI m/z: [MC] calcd for
C26H36O6 444.2512; found 444.2512; IR (KBr) 2946, 1721,
4.5.2. Methyl 2-methyl-4-oxo-1-oxaspiro[4.5]dec-2-en-3-
carboxylate 4b. Hexane/ethyl acetateZ2:1. Colorless oil.
1H NMR (CDCl3) d 1.33–1.42 (1H, m), 1.57–1.81 (9H, m),
2.63 (3H, s), 3.83 (3H, s); 13C NMR (CDCl3) d 18.0, 21.4,
24.3, 31.6, 51.5, 92.2, 107.1, 163.7, 195.3, 201.2; HRMS-EI
m/z: [MC] calcd for C12H16O4 224.1049; found 224.1048;
IR (KBr) 2939, 1709, 1593, 1442, 1199 cmK1
.
4.5.3. Methyl 8-tert-butoxycarbonyl-2-methyl-4-oxo-1-
oxa-8-azaspiro[4.5]dec-2-en-3-carboxylate 4c. Hexane/
ethyl acetateZ2:1. Colorless needles. Mp 110 8C (hexane/
AcOEt); H NMR (CDCl3) d 1.48 (9H, s), 1.50–1.63 (2H,
1675, 1437, 1196 cmK1
.
1
d-like, br), 1.89–1.97 (2H, m), 2.66 (3H, s), 3.15 (2H, br),
3.84 (3H, s), 4.11 (2H, br); 13C NMR (CDCl3) d 18.0, 28.4,
31.3, 39.3 (br), 51.7, 80.1, 89.4, 107.5, 154.5, 163.2, 195.5,
198.7; HRMS-EI m/z: [MC] calcd for C16H23NO6
325.1525; found 325.1536; IR (KBr) 2871, 1705, 1604,
4.6.2. Steroidal spiro orthoester 2j. Hexane/ethylacetateZ
30:1. Colorless needles. Mp 129 8C (MeOH); mixture of two
diastereomaers (ratioZ5:1). 1H NMR (CDCl3) (major
diastereomer) d 0.98 (3H, s), 1.32–1.60 (5H, m), 1.67 (3H,
s), 1.71–2.32 (7H, m), 2.84–3.00 (3H, m), 3.21 (3H, s), 3.64
(3H, s), 3.77 (3H, s), 5.65 (1H, s), 6.63 (1H, br s), 6.69 (1H, dd,
JZ8.8, 1.6 Hz), 7.15 (1H, d, JZ8.8 Hz); (minor diastereo-
mer) d 0.95, 1.61, 3.40, 3.63, 3.77 (s each, Me), 5.54
1426, 1167 cmK1
.
4.5.4. Methyl 2,5-dimethyl-4-oxo-5-(1-phenylethyl)-4,5-
dihydrofuran-3-carboxylate 4d. Hexane/ethyl acetateZ

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K. Kato et al. / Tetrahedron 62 (2006) 2545–2554
(s, C]CH); 13C NMR (CDCl3) (major diastereomer) d 14.8,
24.1, 24.6, 26.4, 27.6, 29.8, 32.3, 33.8, 39.2, 43.4, 48.8, 50.3
(2C), 51.2, 55.2, 93.4, 98.3, 111.5, 113.8, 120.9, 126.2, 132.3,
138.0, 157.5, 166.7, 169.9; EI-MS m/z: 442 (MC); IR (KBr)
2937, 1722, 1650, 1252, 1082, 1049 cmK1. Anal. Found: C,
70.37; H, 7.83 Calcd for C26H34O6: C, 70.56; H, 7.74%.
4.7.2. Methyl 17-acetoxy-3-methoxy-20-oxo-19-nor-
pregna-1,3,5(10)-trien-21-carboxylate 3j. Hexane/ethyl
acetateZ10:1. Colorless needles. Mp 168 8C (MeOH); H
1
NMR (CDCl3) d 1.04 (3H, s), 1.35–1.69 (7H, m), 1.88–1.91
(3H, m), 2.10–2.17 (1H, m), 2.13 (3H, s), 2.31–2.46 (1H, m),
2.79–2.87 (3H, m), 3.41 (1H, d, JZ15.6 Hz), 3.61 (1H, d, JZ
15.6 Hz), 3.74 (3H, s), 3.76 (3H, s), 6.62 (1H, d, JZ2.4 Hz),
6.69 (1H, dd, JZ8.4, 2.4 Hz), 7.14 (1H, d, JZ8.4 Hz); 13C
NMR (CDCl3) d 15.0, 21.1, 24.3, 26.2, 27.3, 29.7, 33.4, 33.6,
38.9, 43.0, 46.0, 46.5, 48.4, 52.3, 55.2, 96.2, 111.5, 113.8,
126.2, 132.1, 137.9, 157.5, 167.4, 171.4, 202.7; EI-MS m/
z: 428 [MC]; IR (KBr) 2946, 1754, 1610, 1501, 1251,
1033 cmK1. Anal. Found: C, 69.97; H, 7.57 Calcd for
C25H32O6: C, 70.07; H, 7.53%.
4.6.3. Steroidal spiro orthoester 2k. Hexane/ethyl acetateZ
20:1. Colorless needles. Mp 172 8C (hexane/CHCl3); mixture
of two diastereomaers (ratioZ5:1). 1H NMR (CDCl3) (major
diastereomer) d 0.96 (3H, s), 1.24–1.74 (7H, m), 1.67 (3H, s),
1.91–2.28 (5H, m), 2.73–2.98 (3H, m), 3.20 (3H, s), 3.63 (3H,
s), 4.80 (1H, br), 5.63 (1H, s), 6.53 (1H, d, JZ2.4 Hz), 6.59
(1H, dd, JZ8.4, 2.4 Hz), 7.07 (1H, d, JZ8.4 Hz); (minor
diastereomer) d 0.93, 1.59, 3.38, 3.62 (s each, Me), 5.54 (s,
C]CH); 13C NMR (CDCl3) (major diastereomer) d 14.8,
24.1, 24.6, 26.4, 27.5, 29.6, 32.3, 33.8, 39.1, 43.3, 48.8, 50.2
(2C), 51.3, 93.4, 98.3, 112.6, 115.2,120.9, 126.4,132.3,138.2,
153.4, 166.8, 169.9; EI-MS m/z: 428 (MC); IR (KBr) 3444,
2932, 1723, 1689, 1644, 1199, 1126 cmK1. Anal. Found: C,
68.31; H, 7.61 Calcd for C25H32O61/2H2O: C, 68.68; H,
7.60%.
4.7.3. Methyl 17-acetoxy-3-hydroxy-20-oxo-19-nor-
pregna-1,3,5(10)-trien-21-carboxylate 3k. Hexane/ethyl
acetateZ3:1. Colorless needles. Mp 189 8C (hexane/
1
AcOEt); H NMR (CDCl3) d 1.02 (3H, s), 1.29–1.69 (7H,
m), 1.82–2.03 (4H, m), 2.14 (3H, s), 2.21–2.26 (1H, m),
2.77–2.86 (3H, m), 3.43 (1H, d, JZ15.6 Hz), 3.62 (1H, d,
JZ15.6 Hz), 3.75 (3H, s), 5.18 (1H, br), 6.55 (1H, d, JZ
2.4 Hz), 6.61 (1H, dd, JZ8.4, 2.4 Hz), 7.04 (1H, d, JZ
8.4 Hz); 13C NMR (CDCl3) d 15.0, 21.1, 24.3, 26.1, 27.2,
29.5, 33.4, 33.6, 38.8, 42.8, 46.1, 46.5, 48.4, 52.4, 96.2,
112.7, 115.3, 126.4, 132.0, 138.1, 153.6, 167.8, 171.5,
202.8; HRMS-EI m/z: [MC] calcd for C24H30O6 414.2042;
found 414.2034; IR (KBr) 3467, 2947, 1739, 1252,
1024 cmK1. Anal. Found: C, 69.08; H, 7.26 Calcd for
C24H30O61/4H2O: C, 68.80; H, 7.34%.
4.6.4. Steroidal spiro orthoester 2l. Hexane/ethyl acetateZ
20:1. Colorless needles. Mp 129 8C (MeOH); mixture of two
diastereomaers (ratioZ5:1). 1H NMR (CDCl3) (major
diastereomer) d 0.95 (3H, s), 1.30–1.55 (6H, m), 1.67 (3H,
s), 1.70–1.81 (1H, m), 1.93–2.23 (5H, m), 2.25 (3H, s), 2.82–
2.98 (3H, m), 3.19 (3H, s), 3.62 (3H, s), 5.63 (1H, s), 6.77 (1H,
d, JZ2.4 Hz), 6.82 (1H, dd, JZ8.4, 2.4 Hz), 7.21 (1H, d, JZ
8.4 Hz); (minor diastereomer) d 0.93, 1.59, 2.02, 3.38 (s each,
Me), 5.54 (s, C]CH); 13C NMR (CDCl3) (major diaster-
eomer) d 14.7, 21.1, 24.1, 24.6, 26.2, 27.3, 29.5, 32.3, 33.7,
38.8, 43.5, 48.8, 50.2, 50.2, 51.2, 93.4, 98.2, 118.5, 120.9,
121.5,126.2,137.7,138.2,148.4,166.7,169.8(2C);EI-MSm/
z: 470 (MC); IR (KBr) 2931, 1767, 1721, 1651, 1206, 1082,
1047 cmK1. Anal. Found: C, 68.86; H, 7.33 Calcd for
C27H34O7: C, 68.92; H, 7.28%.
4.8. Preparation of spiro furanones 4i–4k
4.8.1. 40-Methoxycarbonyl-50-methyl-(17S)-spiro[an-
drost-4-ene-17,20-(30H)-furan]-3,30-dione 4i. Hexane/ethyl
acetateZ2:1. Colorless needles. Mp 194 8C (hexane/AcOEt);
1H NMR (CDCl3) d 0.92–1.17 (2H, m), 1.00 (3H, s), 1.13 (3H,
s), 1.29–1.63 (6H, m), 1.78–1.96 (3H, m), 2.00–2.40 (8H, m),
2.57 (3H, s), 3.77 (3H, s), 5.69 (1H, s); 13C NMR (CDCl3) d
15.1, 17.4, 17.6, 20.3, 23.9, 31.2, 31.2, 31.4, 32.6, 33.8, 35.4,
35.6, 38.4, 47.5, 48.6, 51.4, 52.7, 100.5, 107.7, 124.0, 163.3,
170.5, 196.2, 199.2, 200.5; EI-MS m/z: (MC); 412; IR (KBr)
2941, 1704, 1584, 1438, 1402 cmK1. Anal. Found: C, 72.86;
H, 7.74 Calcd for C25H32O5: C, 72.79; H, 7.82%.
4.7. Preparation of g-hydroxy-b-ketoesters 3i–3k
A solution of the orthoester 2 (0.27 mmol) in MeOH
(10 mL), H2O (0.5 mL) and 10% HCl aq (0.5 mL) was
stirred for the appropriate period of time, the mixture was
diluted with EtOAc (30 mL) and H2O (30 mL). The organic
layer was dried over MgSO4. The solution was concentrated
under reduced pressure. The crude product was purified by
column chromatography on silica-gel. The fraction eluted
with hexane–ethyl acetate (10/1–2/1) afforded 3i–3k.
4.8.2. 40-Methoxycarbonyl-50-methyl-(17S)-spiro[3-
methoxyestra-1,3,5-(10)-triene-17,20(30H)-furan]-30-one
4j. Hexane/ethyl acetateZ5:1. Colorless needles. Mp
1
144 8C (hexane/AcOEt); H NMR (CDCl3) d 1.03 (3H, s),
1.40–1.64 (6H, m), 1.88–2.22 (4H, m), 2.23–2.39 (3H, m),
2.62 (3H, s), 2.84–2.87 (2H, m), 3.77 (3H, s), 3.82 (3H, s),
6.62 (1H, d, JZ1.6 Hz), 6.69 (1H, dd, JZ8.8, 1.6 Hz), 7.14
(1H, d, JZ8.8 Hz); 13C NMR (CDCl3) d 15.2, 17.7, 23.8,
26.0, 27.4, 29.8, 31.4, 31.6, 38.7, 42.9, 47.2, 49.3, 51.5,
55.2, 101.0, 107.7, 111.5, 113.8, 126.3, 132.3, 137.9, 157.5,
163.5, 196.2, 200.8; EI-MS m/z: 410 (MC); IR (KBr) 2939,
1741, 1706, 1601, 1402, 1146 cmK1. Anal. Found: C, 73.09;
H, 7.41 Calcd for C25H30O5: C, 73.15; H, 7.37%.
4.7.1. Methyl 17-acetoxy-3,20-dioxo-pregna-4-en-21-car-
boxylate 3i. Hexane/ethyl acetateZ2:1. Colorless needles.
Mp 61 8C (MeOH); 1H NMR (CDCl3) d 0.85–1.47 (6H, m),
1.02 (3H, s), 1.15 (3H, s), 1.55–1.98 (8H, m), 2.10 (3H, s),
2.22–2.42 (4H, m), 2.72–2.80 (1H, m), 3.34 (1H, d, JZ
15.6 Hz), 3.52 (1H, d, JZ15.6 Hz), 3.70 (3H, s), 5.69 (1H, s);
13C NMR (CDCl3) d 15.0, 17.3, 20.6, 21.0, 24.5, 31.4, 32.6,
33.2, 33.3, 33.9, 35.6, 35.7, 38.4, 45.9, 46.9, 47.8, 52.3, 52.7,
95.9, 124.0, 167.3, 170.4, 171.3, 199.2, 202.5; HRMS-EI m/z:
[MC] calcd for C25H34O6 430.2355; found 430.2371; IR
4.8.3. 40-Methoxycarbonyl-50-methyl-(17S)-spiro[3-
hydroxyestra-1,3,5-(10)-triene-17,20(30H)-furan]-30-one
4k. Hexane/ethyl acetateZ2:1. Colorless needles. Mp
(KBr) 2948, 1741, 1671, 1253, 1029 cmK1
.
272 8C (hexane/AcOEt); H NMR (CDCl3) d 1.01 (3H, s),
1

K. Kato et al. / Tetrahedron 62 (2006) 2545–2554
2553
reviews: (c) Nakamura, I.; Yamamoto, Y. Chem. Rev. 2004,
104, 2127. (d) Zeni, G.; Larock, R. C. Chem. Rev. 2004, 104,
2285. (e) Alonso, F.; Beletskaya, I. P.; Yus, M. Chem. Rev.
2004, 104, 3079. (f) Tietze, L. F.; Ila, H.; Bell, H. P. Chem.
Rev. 2004, 104, 3453. (g) Soderberg, B. C. G. Coord. Chem.
Rev. 2004, 248, 1085. (h) Vizer, S. A.; Yerzhanov, K. B.;
Quntar, A. A. A. A.; Dembitsky, V. M. Tetrahedron 2004, 60,
5499. (i) Muzart, J. Tetrahedron 2005, 61, 5955.
1.34–1.66 (6H, m), 1.85–1.95 (3H, m), 2.05–2.30 (4H, m),
2.62 (3H, s), 2.79–2.81 (2H, m), 3.84 (3H, s), 5.47 (1H, br),
6.59–6.62 (2H, m), 7.00 (1H, d, JZ7.6 Hz); 13C NMR
(CDCl3) d 15.3, 17.8, 23.8, 25.8, 27.3, 29.6, 31.3, 31.5, 38.4,
42.6, 47.2, 49.4, 51.5, 101.2, 107.7, 113.0, 115.7, 126.4,
132.0, 137.8, 153.6, 163.4, 196.4, 201.3; HRMS-EI m/z:
[MC] calcd for C24H28O5 396.1937; found 396.1934; IR
(KBr) 3349, 2918, 1707, 1684, 1584, 1443, 1160 cmK1
.
2. (a) Yoshida, M.; Fujita, M.; Ishii, T.; Ihara, M. J. Am. Chem.
Soc. 2003, 125, 4874. (b) Labrosse, J.-R.; Lhoste, P.; Snou, D.
J. Org. Chem. 2001, 66, 6634. (c) Condon-Gueugnot, S.;
Linstrumelle, G. Tetrahedron 2000, 56, 1851. (d) Ackermann,
L.; Bruneau, C.; Dixneuf, H. P. Synlett 2001, 397. (e) Tsuji, J.;
Mandai, T. Angew. Chem., Int. Ed. Engl. 1995, 34, 2830.
3. (a) Ehud, K.; Eric, B. J. Org. Chem. 1986, 51, 4006.
(b) Tsuji, J.; Watanabe, H.; Minami, I.; Shimizu, I. J. Am.
Chem. Soc. 1985, 107, 2196.
Anal. Found: C, 72.3; H, 7.12 Calcd for C24H28O5: C, 72.7;
H, 7.12%.
4.9. NMR experiments
To a stirred solution of 1b (10 mg, 0.06 mmol) in CD2Cl2
(0.5 mL) was added (CH3CN)2PdCl2 (16 mg, 0.06 mmol).
After the (CH3CN)2PdCl2 dissolved completely (ca. 5 min),
the spectra was measured immediately.
4. (a) Bartels, A.; Mahrwald, R.; Muller, K. Adv. Synth. Catal.
2004, 346, 483. (b) Kataoka, H.; Watanabe, K.; Goto, K.
Tetrahedron Lett. 1990, 31, 4181. (c) Mahrwald, R.;
Schick, H. Angew. Chem., Int. Ed. Engl. 1991, 30, 593.
(d) Rautenstrauch, V. J. Org. Chem. 1984, 49, 950.
1H NMR (CD2Cl2) d 1.41–1.64 (5H, m), 1.77–1.94 (4H, m),
1.97 (6H, s, CH3CN), 1.99–2.07 (1H, m), 2.29 (3H, s), 5.47
(1H, s); 13C NMR (CD2Cl2) d 2.0, 20.5, 26.5, 27.3, 30.0,
31.8, 34.9, 72.4, 94.1, 116.9, 128.0, 168.5.
5. (a) Bacchi, A.; Costa, M.; Ca, N. D.; Gabriele, B.; Salerno, G.;
Cassoni, S. J. Org. Chem. 2005, 70, 4971. (b) Mandai, T.;
Tsujiguchi, Y.; Matsuoka, S.; Saito, S.; Tsuji, J. J. Organomet.
Chem. 1995, 488, 127.
4.10. Method for the biological activity test (1)
All experiments comply with the Guiding Principles for the
Care and Use of Laboratory Animals Approved by the
Japanese Pharmacological Society. The right atria was
rapidly isolated from 1 to 3 day old chicks and beating rate
measurements were performed as described previously.26
The aorta was rapidly isolated from male rats (350–450 g)
and contractile force measurements with endothelium-
denuded aortic rings were performed as described pre-
viously.26 The test compounds were dissolved in DMSO and
small alliquots were applied to the organ bath to yield a final
concentration of 10K5 M.
6. (a) Kato, K.; Nishimura, A.; Yamamoto, Y.; Akita, H.
Tetrahedron Lett. 2001, 42, 4203. (b) Kato, K.; Tanaka, M.;
Yamamoto, Y.; Akita, H. Tetrahedron Lett. 2002, 43, 1511.
7. Kato, K.; Yamamoto, Y.; Akita, H. Tetrahedron Lett. 2002, 43,
4915.
8. For a preliminary communication of this work see: Kato, K.;
Yamamoto, Y.; Akita, H. Tetrahedron Lett. 2002, 43, 6587.
9. (a) Kato, K.; Nishimura, A.; Yamamoto, Y.; Akita, H.
Tetrahedron Lett. 2002, 43, 643. (b) Kato, K.; Sasaki, T.;
Takayama, H.; Akita, H. Tetrahedron 2003, 59, 2679. (c)
Sasaki, T.; Kato, K.; Akita, H. Chem. Pharm. Bull. 2004, 52,
770. (d) Akita, H.; Sasaki, T.; Kato, K.; Suzuki, Y.; Kondo, K.;
Sakagami, Y.; Ojika, M.; Fudou, R.; Yamanaka, S. Tetra-
hedron 2004, 60, 4735.
4.11. Method for the biological activity test (2)
Assay for CYP3A activity (midazolam 10-hydroxylation)
was assessed according to a previously published proce-
dure.27 Hepatic microsomes isolated from male Splague–
Dawley rats (250 g) was preincubated with 3!10K5 M of
the test compounds and 1 mM NADPH at 37 8C for 20 min,
before assaying for CYP3A activity.
10. Frey, H.; Kaupp, G. Synthesis 1990, 931.
11. Asao, N.; Nogami, T.; Takahashi, K.; Yamamoto, Y. J. Am.
Chem. Soc. 2002, 124, 764.
12. Kato, K.; Tanaka, M.; Yamamura, S.; Yamamoto, Y.;
Akita, H. Tetrahedron Lett. 2003, 44, 3089.
13. Binotti, B.; Carfagna, C.; Foresti, E.; Macchioni, A.;
Sabatino, P.; Zuccaccia, C.; Zuccacia, D. J. Organomet.
Chem. 2004, 689, 647.
Acknowledgements
14. Moncarz, J. R.; Brunker, T. J.; Jewett, J. C.; Orchowski, M.;
Glueck, D. S. Organometallics 2003, 22, 3205.
We are grateful for the financial support of the Eisai Award
in Synthetic Organic Chemistry Japan (2002), Takeda
Science Foundation (2003) and The Research Foundation
for Pharmaceutical Sciences (2002).
15. NMR chemical shifts of the proposed complex A have been
estimated using the GIAO method as implemented in Gaussian
98 (Gaussian, Inc., Pittsburg). 13C NMR shifts: d 2.5 (CH3CN),
2.6 (CH3CN), 21.6 (–CH2–), 21.9 (–CH2–), 24.9 (–CH2–), 34.3
(CH3), 41.2 (–CH2–), 44.1 (–CH2–), 76.1, 122.7 (O–C]C–
Pd), 129.9 (O–C–O), 148.7 (CH3CN), 149.3 (CH3CN), 166.0
(O–C]C–Pd). Calculations were performed at the HF/
Lanl2DZ level at a PM3-optimized (Spartan 04; Wavefunc-
tion, Inc.) geometry.
References and notes
1. (a) Tsuji, J. Palladium Reagents and Catalysts; Wiley:
Chichester, 1995; p 19. (b) Stille, J. K. In Trost, B. M.,
Fleming, I., Eds.; Comprehensive Organic Synthesis;
Pergamon: New York, 1991; Vol. 4, p 913. For recent
16. (a) Langer, P.; Krummel, T. Chem. Eur. J. 2001, 7, 1720. (b)
Aoki, S.; Oi, T.; Shimizu, K.; Shiraki, R.; Takao, K.; Tadano,
K. Bull. Chem. Soc. Jpn. 2004, 77, 1703. (c) Drina, G. J.;
Sampson, P.; Wiemer, D. F. Tetrahedron Lett. 1984, 25, 4467.

2554
K. Kato et al. / Tetrahedron 62 (2006) 2545–2554
17. (a) Smith, A. B., III; Levenberg, P. A.; Jerris, P. J.;
Scarborough, R. M.; Wovkulich, P. M. J. Am. Chem. Soc.
1981, 103, 1501. (b) Jerris, P. J.; Smith, A. B., III J. Org.
Chem. 1981, 46, 577. (c) Gelin, S.; Chabannet, M. Synthesis
1987, 448. (d) Babin, P.; Dunogues, J.; Duboudin, F.; Petraud,
M. Bull. Soc. Chem. Fr. 1982, 3–4, 125. (e) Sebti, S.; Foucaud,
A. Tetrahedron 1986, 42, 1361. (f) Villemin, D.; Jaffres, P.-A.;
Hachemi, M. Tetrahedron Lett. 1997, 38, 537. Steroidal C-17
spirofuranones: (g) Ortar, G.; Morera, E. J. Org. Chem. 1981,
46, 452. (h) Barannovsky, A. V.; Groen, M. B.; Groot, A. D.;
Litvinovskaya, R. P.; Khripach, V. A. Collect. Czech. Chem.
Commun. 1998, 63, 1564. Palladium catalyzed synthesis: (i)
Inoue, Y.; Taniguchi, M.; Hashimoto, H.; Ohuchi, K.;
Imaizumi, S. Chem. Lett. 1988, 81. (j) Kiji, J.; Okano, T.;
Kimura, H.; Saiki, K. J. Mol. Catal. A: Chem. 1998, 130, 95.
(k) Reiter, M.; Turner, H.; Mills-Webb, R.; Gouverneur, V.
J. Org. Chem. 2005, 70, 8478.
22. Mack, R. A.; Zazulak, W. I.; Radov, L. A.; Baer, J. E.; Stewart,
J. D.; Elzer, P. H.; Kinsolving, C. R.; St. Georgiev, V. J. Med.
Chem. 1988, 31, 1910.
23. 1a: Kolt, R. J.; Griller, D.; Wayner, D. D. M. Tetrahedron
Lett. 1990, 31, 7539. 1b: Orita, A.; Tanahashi, C.; Kakuda, A.;
Otera, J. J. Org. Chem. 2001, 66, 8926. 1c: Kitano, Y.;
Kawahara, E.; Takayanagi, H.; Suzuki, T.; Ohya, A.; Hara, H.
Jpn. Kokai Tokkyo Koho, JP 11080131 A2 19990326 Heisei,
1999, p 235. 1d: O’Hagan, D.; Zaidi, N. A. Tetrahedron:
Asymmetry 1994, 5, 1111. 1e: Kaiser, E. M.; Woodruff, R. A.
J. Org. Chem. 1970, 35, 1198. 1g: Gomez-Vidal, J. M.;
Forrester, M. T.; Silverman, R. B. Org. Lett. 2001, 3, 2477. 1h:
Martinet, P.; Doupeux, H. Compt. Rend. 1964, 259, 2241. 1i:
Turuta, A. M.; Fadeeva, T. M.; Kamernitskii, A. V.;
Cherepanova, E. G.; Luu, D. H. Izv. Akad. Nauk SSSR, Ser.
Khim. 1990, 675. 1j: Bartles, A.; Mahrwald, R.; Muller, K.
Adv. Synth. Catal. 2004, 346, 483. 1k:
Weber, G.;
18. Shin, S. S.; Byun, Y.; Lim, K. M.; Choi, J. K.; Lee, K.-W.;
Moh, J. H.; Kim, J. K.; Jeong, Y. S.; Kim, J. Y.; Choi, Y. H.;
Koh, H.-J.; Park, Y.-H.; Oh, Y. I.; Noh, M.-S.; Chung, S.
J. Med. Chem. 2004, 47, 792.
Schaumann, J.; Carl, C.; Schwarz, S. J. Prakt. Chem. 1989,
331, 223.
24. Sheldrick, G. M. SHELXL97: Program for the Solution for
¨ ¨
Crystal Structures; University of Gottingen: Gottingen,
19. Carotti, A.; Carrieri, A.; Chimichi, S.; Boccalini, M.;
Cosimelli, B.; Gnerre, C.; Carotti, A.; Carrupt, P.-A.;
Testa, B. Bioorg. Med. Chem. Lett. 2002, 12, 3551.
Germany, 1997.
25. ORTEP-3 for Windows Farrugia, L. J. J. Appl. Crystallogr.
1997, 30, 565.
20. Chimichi, S.; Boccalini, M.; Cosimelli, B.; Dall’Acqua, F.;
Viola, G. Tetrahedron 2003, 59, 5215.
26. Tanaka, H.; Masumiya, H.; Sekine, T.; Shijuku, T.; Sugahara,
M.; Taniguchi, H.; Terada, M.; Saito, W.; Shigenobu, K. Gen.
Pharmacol. 1996, 27, 695–701.
21. Sakaki, T.; Yamakoshi, J.; Saito, M.; Kasai, K.; Matsudo, T.;
Kikuchi, M.; Koga, T.; Mori, K. Biosci., Biotechnol., Biochem.
1998, 62, 2145.
27. Prueksaritanont, T.; Gorham, L. M.; Hochman, J.; Tran, L.;
Vyas, K. P. Drug Metab. Dispos. 1996, 24, 634.