Synthetic studies of furanosesquiterpenoid tetrahydrolinderazulenes. Total synthesis of (±)-echinofuran

Article abstract of DOI:10.1016/S0040-4020(03)00181-9

Echinofuran (1) was isolated in 1992 and was reported to inhibit cell division of fertilized sea urchin eggs. The synthesis of 1 was achieved by a Ring A→Ring AC→Ring ABC approach employing 3-methyl-4-(trimethylsilyl)furan (2) as a precursor. A Suzuki cou

Full text of DOI:10.1016/S0040-4020(03)00181-9

Tetrahedron 59 (2003) 1877–1884
Synthetic studies of furanosesquiterpenoid
tetrahydrolinderazulenes. Total synthesis of (6)-echinofuran
Ho-Kee Yim,a,b Yun Liaoa and Henry N. C. Wonga,b,c
,
*
aDepartment of Chemistry, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong SAR, People’s Republic of China
bCentral Laboratory of the Institute of Molecular Technology for Drug Discovery and Synthesis†,
The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong SAR, People’s Republic of China
cInstitute of Chinese Medicine, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong SAR, People’s Republic of China
Received 17 October 2002; revised 7 January 2003; accepted 30 January 2003
Dedicated to Professor Al Padwa on the occasion of his 65th birthday
Abstract—Echinofuran (1) was isolated in 1992 and was reported to inhibit cell division of fertilized sea urchin eggs. The synthesis of 1 was
achieved by a Ring A!Ring AC!Ring ABC approach employing 3-methyl-4-(trimethylsilyl)furan (2) as a precursor. A Suzuki coupling
reaction and a Lewis acid mediated Friedel-Crafts cyclization were the other key steps in the construction of the ring systems. In other
preliminary model studies, two furan-containing 5,7,5-fused tricyclic molecules were also realized. q 2003 Elsevier Science Ltd. All rights
reserved.
1. Introduction
Ring A!Ring AC!Ring ABC was designed to construct
the target molecule 1 (Fig. 1). The key steps involved are the
Suzuki-type cross-coupling reaction,9,10 which is respon-
sible for the formation of Ring AC and the Lewis acid
promoted Friedel-Crafts acylation, which is responsible for
the formation of Ring ABC.
In recent years, many sesquiterpene metabolites were
identified from species of gorgonians.1 These compounds
have been shown to exhibit interesting biological activities
including cytotoxicity, antifungal activity, and immuno-
stimulatory activity.2 Echinofuran (1),3 a kind of furano-
sesquiterpenoid tetrahydrolinderazulene isolated from the
gorgonian Echinogorgia praelonga, was found to inhibit
cell division of fertilized sea urchin eggs.4
2. Result and discussion
Herein, we would like to employ our own organosilicon–
organoboron protocol devised towards the synthesis of 3,4-
disubstituted furans to achieve the total synthesis of
echinofuran (1).5,6 It is noteworthy that similar approaches
have been employed by Tanis7 and Schultz8 in their quests
of pseudoquaianolide sesquiterpenes. In our own synthetic
approach, a route involving the sequential construction of
As depicted in Scheme 1, our strategy makes use of 3-
methyl-4-(trimethylsilyl)furan (2)5f,11 as the precursor,
which in turn was prepared by a Diels–Alder reaction
between 4-phenyloxazole12 and 1-trimethylsilylpropyne
with concomitant extrusion of benzonitrile5f under high
temperature and pressure. Furan 2 was converted to
boroxine 3 upon reaction with boron trichloride.5f As
expected, 3 smoothly underwent a regiospecific Suzuki
cross-coupling reaction with ethyl 4-bromo-3-methoxy-
crotonate13 to give ester 4. After hydrolysis, b-ketoester 5
was obtained and a route involving alkylation-intra-
molecular Wittig cyclization was designed by utilizing
3-iodopropyltriphenylphosphonium iodide,14 leading to
ester 6 that provided the basic structure of Ring AC.
Figure 1.
In order to construct the central seven-membered ring, one
more carbon was required at the ethyl ester side chain of 6.
Acid 9 was eventually obtained from 6 via 7 and 8 by a
classical nucleophilic substitution method illustrated in
Scheme 2.
Keywords: furan; tricyclic; Lewis acid cyclization.
*
Corresponding author. Tel.: þ852-2609-6329; fax: þ852-2603-5057;
e-mail: hncwong@cuhk.edu.hk
An Area of Excellence of the University Grants Committee (Hong Kong).
†
0040–4020/03/$ - see front matter q 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4020(03)00181-9

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H.-K. Yim et al. / Tetrahedron 59 (2003) 1877–1884
Scheme 1. Reagents and conditions. (a) (i) BCl3, CH2Cl2, 2788C, 6 h, (ii) 2 M Na2CO3, 2 h. (b) Ethyl 4-bromo-3-methoxycrotonate, Pd(PPh3)4, 2 M K3PO4,
THF, reflux. (c) p-TsOH, EtOH–H2O (1:1). (d) 3-Iodopropyltriphenylphosphonium iodide, K2CO3, CH2Cl2, 18-crown-6, reflux.
Without further purification acid 9 was immediately
subjected to an intramolecular Friedel-Crafts acylation.
Trifluoroacetic anhydride (TFAA) was found to be the most
effective reagent in promoting the cyclization,15 leading to
the formation of the cycloheptenone 10 (Ring ABC).
Despite the meager yield of the TFAA-catalyzed cycliza-
tion, the synthesis of 10 has nonetheless provided a viable
approach towards tetrahydrolinderazulenes. However, the
total synthesis of 1 may require more efficient and elaborate
synthetic routes. Consequently, we initiated a new program
to study alternative cyclization reactions of furans towards
the formation of seven-membered rings.
Like other aromatic compounds, furans are able to undergo
electrophilic substitutions. However, due to the low stability
of furan-containing compounds, low reaction temperatures
and mild catalysts are usually required. In our model
studies, we placed our attention on improving the efficiency
of the cyclization by altering the structure of Ring C in the
hope of enhancing the intramolecular cyclization. In this
connection, we generated dienone 15 through four steps
starting from 1,3-cyclopentanedione (11), a commercially
available starting material (Scheme 3). According to the
literature,16 1,3-cyclopentanedione (11) was converted to
1,3-dioxin 12 and was followed by an alkylative 1,3-ketone
Scheme 2. Reagents and conditions. (a) LiAlH4, THF. (b) NBS, PPh3, DMF. (c) (i) KCN, 18-crown-6, CH3CN, (ii) NaOH, MeOH, reflux, (iii) 1 M HCl. (d)
TFAA, CH2Cl2, 08C.
t
Scheme 3. Reagents and conditions. (a) (CH2O)n, BF3–Et2O, CH2Cl2. (b) (i) 2-Bromopropene, BuLi, THF, 2788C, (ii) 2N HCl. (c) PBr3, Et2O, 08C. (d)
Boroxine 3, Pd(PPh3)4, 2 M K3PO4, THF, reflux.

H.-K. Yim et al. / Tetrahedron 59 (2003) 1877–1884
1879
Table 1.
Although 16 did not lead us to 1, it may still serve as a
useful intermediate towards the preparation of
tetrahydrolinderazulenes.
Ester 19 was synthesized in the same way as that for 15
through three steps from 1,3-dioxin 12 (Scheme 4). 1,3-
Cyclopentanedione (11) was converted to 1,3-dioxin 12 and
was followed by an alkylative 1,3-ketone transposition to
afford alcohol 17. After bromination of 17, the resulting
bromide 18 was allowed to undergo a Suzuki coupling with
3, affording 19.
Reagents
Temperature (8C)
Time (h)
Yield (%)
FeCl3
TiCl4
BF3–Et2O
EtAlCl2
Et2AlCl
0, 278
0, 278
0, 278
220
0.1
0.1
0.1
15
0a,b
0b
0b
40
65
To complete our total synthesis of 1, enone 19 was first
reduced to enol 20 by NaBH4 and the resulting hydroxyl
group was protected as benzyl ether 21. Saponification of 21
with NaOH was followed immediately without further
purification by a Friedel-Crafts cyclization, leading to 22,
with the desired Ring ABC skeleton very similar to our
target molecule. An isomerization reaction was undertaken
to convert the b,g-unsaturated ketone 22 to an a,b-
unsaturated ketone 23. An efficient isomerization procedure
was carried out on exposure of 22 to 2.5 mol equiv. of DBU
in CH2Cl2, affording 23 in 65% yield (Scheme 5).
0
10
a
20% of 15 was recovered.
Polymerization.
b
The conversion of 22 to 23 was easily observed by both 1H
and 13C NMR spectroscopic methods. By comparing the 1H
NMR spectrum of 23 with 22, it was found that the signal of
H-12 changed from a doublet to a singlet. In addition, the
13C NMR spectrum of 23 revealed that the formation of an
a,b-unsaturated ketone caused an upshield shift of 10 ppm
for the carbonyl absorption at C-9.
Scheme 4. Reagents and conditions. (a) (i) Ethyl propionate, LDA, THF,
2788C, (ii) 2N HCl. (b) PBr3, Et2O, 08C. (c) Boroxine 3, Pd(PPh3)4, 2 M
K3PO4, THF, reflux.
The final stage of our synthetic route featured three main
steps including (i) removal of the carbonyl group at Ring B,
(ii) deprotection of the benzyl group at Ring C and (iii)
oxidation and methylenation. As depicted in Scheme 6, the
carbonyl group at Ring B was removed by reduction to an
alcohol and followed by mesylation. The mesylate was
reduced further with LiAlH4 to form 24. The deprotection of
benzyl ether 24 led to alcohol 25, whose hydroxyl group
was oxidized to a carbonyl group with IBX,18 affording the
b,g-unsaturated ketone 26. The total synthesis of (^)-
echinofuran (1) was finally achieved by formation of the
exomethylene group at Ring C by Peterson olefination.
transposition to afford alcohol 13. After bromination of 13,
the resulting bromide 14 was allowed to undergo a Suzuki
coupling with 3, affording 15 whose conjugated dienone
framework was believed to facilitate the Lewis acid
catalyzed cyclization.17
Thus, different reaction conditions were attempted to
convert 15 to 16 (Table 1). As can be seen, weak Lewis
acid and low temperature were both needed to secure a
better yield of 16. With 16 (Ring ABC) in hand, attempts
had been made in vain to achieve our target compound 1, the
major difficulty being the position of the C–C double bond.
In conclusion, the first total synthesis of (^)-echinofuran (1)
was accomplished in 12 steps with a total yield of 0.55%.
Scheme 5. Reagents and conditions. (a) NaBH4, CeCl3, MeOH. (b) BnBr, NaH, DMF. (c) (i) NaOH, MeOH, reflux, (ii) TFAA, CH2Cl2, 08C. (d) DBU
(2.5 equiv.), CH2Cl2, 2788C.

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H.-K. Yim et al. / Tetrahedron 59 (2003) 1877–1884
Scheme 6. Reagents and conditions. (a) (i) NaBH4, MeOH, 08C, (ii) MsCl, Et3N, CH2Cl2, (iii) LiAlH4, ether, reflux. (b) (i) BBr3, CH2Cl2, 2788C, (ii) MeOH,
08C. (c) IBX, CH2Cl2. (d) (i) Me3SiCH2MgCl, ether, (ii) NaH, THF, reflux.
We are also of the opinion that our study on the formation of
the furan-containing 5,7,5-fused tricyclic molecules will be
invaluable towards the synthesis of other naturally occur-
ring furanosesquiterpenoid tetrahydrolinder-azulenes.
13 mmol). After refluxing for 3 days, the mixture was
filtered. The solvent was removed to give a viscous oil,
which was then purified by column chromatography on
silica gel (100 g, hexanes/EtOAc, 45:1) to afford 6 (0.8 g,
34%) as a colorless oil: 1H NMR (C6D6) d 7.27 (d,
J¼1.2 Hz, 1H), 7.22 (d, J¼1.5 Hz, 1H), 5.38 (q, J¼1.8 Hz,
1H), 4.00 (dq, J¼0.8, 6 Hz, 2H), 3.45 (m, 3H), 2.39 (m, 4H),
1.95 (s, 3H), 0.99 (t, J¼6 Hz, 3H); 13C NMR (CDCl3) d
174.8, 148.2, 140.8, 140.7, 129.7, 125.8, 119.2, 60.4, 52.2,
31.4, 28.3, 26.0, 14.2, 8.6. Anal. calcd for C14H18O3: C,
71.77; H 7.14. Found: C, 71.87; H, 7.27.
3. Experimental
3.1. General information
All reagents and solvents were reagent grade. Further
purification and drying by standard methods were employed
when necessary. All organic solvents were evaporated under
reduced pressure with a rotary evaporator. The plates used
for thin-layer chromatography (TLC) were E. Merck silica
gel 60F254 (0.25 mm thickness) precoated on aluminum
plates, and they were visualized under both long (365 nm)
and short (254 nm) UV light. Compounds on TLC plates
were visualized with a spray of 5% dodecamolybdophos-
phoric acid in ethanol and with subsequent heating. Column
chromatography was performed using E. Merck silica gel
(230–400 mesh).
3.1.2. [2-(4-Methylfuran-3-yl)methyl]cyclopent-2-ene-1-
methanol (7). To a solution of 6 (0.4 g, 1.3 mmol) in THF
(20 mL) was added lithium aluminum hydride (1 M in THF,
1.5 mL) under N2. After stirring at room temperature for
3 h, it was cooled to 08C and quenched with absolute EtOH.
Upon removal of solvent, the residue was column
chromatographed on silica gel (100 g, hexanes/EtOAc,
1
20:1) to afford 7 (0.2 g, 64%) as a colorless oil: H NMR
(C6D6) d 7.22 (d, J¼4 Hz, 1H), 7.20 (d, J¼4 Hz, 1H), 5.34
(d, J¼1.5 Hz, 1H), 3.43 (dq, J¼5, 12 Hz, 2H), 3.29 (d,
J¼17 Hz, 1H), 3.14 (d, J¼17 Hz, 1H), 2.60 (s, 1H), 2.30–
2.10 (m, 3H), 1.98 (m, 4H), 1.74 (m, 1H); 13C NMR
(CDCl3) d 148.3, 142.3, 140.6, 128.8, 126.2, 119.2, 64.6,
49.2, 30.8, 27.3, 25.8, 8.6. Anal. calcd for C12H16O2: C,
74.97; H 8.39. Found: C, 74.81; H, 8.34.
NMR spectra were recorded on a Bruker DPX-300
spectrometer (300.13 MHz for 1H and 75.47 MHz for
13C). All NMR measurements were carried out at 300 K
in deuterated chloroform solution unless otherwise stated.
Chemical shifts are reported as parts per million (ppm) in d
unit in the scale relative to the resonance of CDCl3
3.1.3. 3-[1-(5-Bromomethylcyclopent-1-enyl)methyl]-4-
methylfuran (8). To a solution of 7 (62 mg, 0.25 mmol)
in DMF (5 mL), N-bromosuccinimide (90 mg, 0.5 mmol)
and triphenylphosphine (135 mg, 0.5 mmol) were added at
room temperature. After stirring for 3.5 h, the reaction
mixture was quenched with MeOH. The solvent was
removed under reduced pressure and the residue was further
purified by column chromatography on silica gel (30 g,
hexanes/EtOAc, 45:1) to afford 9 (57 mg, 73%) as a
1
(7.26 ppm in the H, 77.00 ppm for the central line of the
triplet in the 13C modes, respectively). Coupling constants
(J) are reported in Hz. Splitting patterns are described by
using the following abbreviations: s, singlet; d, doublet; t,
triplet; q, quartet; m, multiplet. 1H NMR data is reported in
this order: chemical shift; multiplicity; coupling constant(s),
number of proton. Mass spectra (ERMS and HRMS) were
obtained with a Thermofinnigan MAT95XL spectrometer
and determined at an ionized voltage of 70 eV unless
otherwise stated. Relevant data were tabulated as m/z.
Elemental analyses were performed at Shanghai Institute of
Organic Chemistry, the Chinese Academy of Sciences,
China.
1
colorless oil: H NMR (C6D6) d7.22 (d, J¼1.2 Hz, 1H),
7.13 (d, J¼1.2 Hz, 1H), 5.37 (q, J¼1.8 Hz, 1H), 3.27–3.02
(m, 4H), 2.75 (s, 1H), 2.30–2.00 (m, 2H), 1.96 (m, 4H), 1.85
(m, 1H); 13C NMR (CDCl3) d 148.4, 142.4, 140.7, 129.4,
125.8, 119.1, 48.5, 37.8, 30.3, 29.3, 25.5, 8.6; HRMS
(FAB) calcd for C12H15OBr (Mþ) 255.0545. Found:
255.0574.
3.1.1. Ethyl [2-(4-methylfuran-3-yl)methyl]cyclopent-2-
ene-1-carboxylate (6). To a mixture of 3-iodopropyl-
triphenylphosphonium iodide12 (11 g, 20 mmol), anhydrous
potassium carbonate (3.8 g, 27 mmol), 18-crown-6 (34 mg,
0.13 mmol) in CH2Cl2 (400 mL) was added 511 (3.5 g,
3.1.4. 4,6,7,7a,8,9-Hexahydro-3-methyl-azulenofuran-9-
one (10). To a solution of 8 (16 mg, 0.05 mmol) in CH3CN
(0.5 mL), potassium cyanide (10 mg, 0.15 mmol) and

H.-K. Yim et al. / Tetrahedron 59 (2003) 1877–1884
1881
18-crown-6 (10 mg) were added at room temperature. After
stirring for 38 h, the solvent was removed under reduced
pressure and the residue was purified by column chroma-
tography on silica gel (10 g, hexanes/EtOAc, 20:1), a
colorless oil was obtained, which was mixed with NaOH
(2 M, 0.2 mL) in MeOH (0.6 mL) and was heated to 908C
for 10 h. After that H2O (0.5 mL) was added and the
resulting mixture was washed with CH2Cl2 (2.0 mL). The
aqueous layer was acidified with HCl (2 M) until the pH
reached 1. It was then extracted with CH2Cl2 (3£5 mL). The
combined organic extract was dried (MgSO4) and evapor-
ated under reduced pressure. The residue 9 was re-dissolved
in anhydrous CH2Cl2 (1.0 mL). Trifluoroacetic anhydride
(0.01 mL, 0.07 mmol) was slowly added. After stirring for
6 h, the reaction mixture was quenched with saturated
aqueous sodium bicarbonate. The organic layer was
separated and the aqueous layer was extracted with
CH2Cl2 (3£3 mL). The combined organic extract was
dried (MgSO4) and evaporated. The residue was purified
by column chromatography on silica gel (10 g, hexanes/
EtOAc, 15:1) to give 10 (1.6 mg, 11%) as colorless oil: 1H
NMR (CDCl3) d 6.96 (s, 1H), 5.36 (t, J¼2 Hz, 1H), 3.50 (m,
3H), 3.08 (m, 2H), 2.25 (m, 2H), 1.99 (m, 5H); 13C NMR
(CDCl3) d 200.6, 147.0, 143.5, 139.0, 131.4, 121.7, 120.7,
60.7, 41.6, 31.7, 28.8, 28.6, 8.8; HRMS (FAB) calcd for
C13H14O2 (Mþ) 202.1233. Found: 202.1223.
3.1.7. 2-(Bromomethyl)-3-(2-propenyl)-2-cyclopente-
none (14). To a solution of 13 (2.00 g, 13 mmol) in
anhydrous Et2O (30 mL) was added slowly PBr3 (0.60 mL,
6.5 mmol) at 08C. After stirring for 30 min, MeOH (5 mL)
was added and the resulting mixture was allowed to stir for
10 min. The solvent was removed under reduced pressure
and the residue was purified by flash column chromato-
graphy on silica gel (60 g, hexanes/EtOAc, 5:1) to afford 14
(2.65 g, 96%) as a pale yellow oil: 1H NMR (CDCl3) d 5.49
(s, 1H), 5.39 (s, 1H), 4.12 (s, 2H), 2.69 (m, 2H), 2.45 (m,
2H) 2.07 (s, 3H); 13C NMR (CDCl3) d 206.8, 171.6, 139.8,
135.6, 120.5, 33.5, 28.7, 21.2, 20.8; HRMS (FAB) calcd for
C9H11OBr (Mþ) 213.9988. Found: 213.9998.
3.1.8. 2-[(3-Methylfuran-4-yl)methyl]-3-(2-propenyl)-2-
cyclopentenone (15). To a refluxing mixture of 14
(2.15 g, 10 mmol), 2 M K3PO4 (5 mL) and Pd(PPh3)4
(0.23 g, 0.20 mmol) in THF (20 mL) was added dropwise
a solution of 3 (1.08 g, 3.33 mmol) in THF (25 mL) under
nitrogen over 2 h. After addition, the mixture was refluxed
for a further 1 h. After filtration, THF was evaporated under
reduced pressure. The aqueous residue was extracted with
Et2O (4£50 mL) and was dried (MgSO4). After removal of
solvent, the residue was purified by flash column chroma-
tography on silica gel (100 g, hexanes/EtOAc, 5:1) to afford
15 (1.12 g, 52%) as a colorless oil: 1H NMR (CDCl3) d 6.99
(d, J¼1.2 Hz, 1H), 6.78 (s, 1H), 5.15 (d, J¼3.6 Hz, 1H),
5.13 (d, J¼1.2 Hz, 1H), 3.24 (s, 2H), 2.61 (m, 2H), 2.34 (m,
2H), 1.89 (d, J¼0.9 Hz, 3H), 1.85 (d, J¼0.9 Hz, 3H); 13C
NMR (CDCl3) d 208.5, 168.9, 140.3, 139.1, 138.9, 137.3,
122.7, 119.1, 118.0, 33.2, 28.2, 20.8, 17.9, 7.6; IR: (thin
film) 3082, 1705, 1640, 1598 cm21; HRMS (EI) calcd for
C14H16O2 (Mþ) 216.1145. Found: 216.1144.
3.1.5. 6,7-Dihydrocyclopenta-1,3-dioxin-5(4H)-one
(12).15
A mixture of 1,3-cyclopentanedione (3.24 g,
33.0 mmol), paraformaldehyde (6.00 g, 200 mmol),
BF3·Et2O (12.6 mL, 100 mmol) and CH2Cl2 (200 mL) was
stirred vigorously at room temperature for 38 h. The mixture
was then filtered and the filtrate added to 10% NaOH
(130 mL) and ice (50 g). The resulting aqueous layer was
extracted with CH2Cl2 (3£75 mL), and the combined
organic phases were washed with brine and was dried
over MgSO4. Removal of the solvent under reduced
pressure and purification of the residue by flash column
chromatography on silica gel (100 g, hexanes/acetone, 3:1)
afforded 12 (3.55 g, 77%) as a white solid; mp 74–768C (lit.
3.1.9. 4,6,7,8,9-Pentahydro-3,8-dimethylauzleno[6,5-
b]furan-5(2H)-one (16). To a solution of dienone 15
(1.08 g, 5 mmol) in anhydrous toluene (20 mL) at 08C was
added rapidly diethylaluminum chloride (1.80 M in toluene,
5.55 mL, 10 mmol). The reaction mixture was stirred for
10 h, and then quenched with NH4Cl (20 mL). The aqueous
layer was extracted with Et2O (3£50 mL) and the combined
organic phases were washed with brine and dried (MgSO4).
After removal of solvent, the residue was purified by flash
column chromatography on silica gel (100 g, hexanes/
EtOAc, 6:1) to afford 16 (0.70 g, 65%) as a pale yellow oil:
1H NMR (CDCl3) d 6.87 (d, J¼1.5 Hz, 1H), 3.48 (d,
J¼0.9 Hz, 2H), 2.94 (m, 1H), 2.85 (m, 1H), 2.68 (m, 1H),
2.58 (m, 2H), 2.37 (m, 2H), 1.99 (d, J¼1.5 Hz, 3H), 1.25 (d,
J¼12 Hz, 3H); 13C NMR (CDCl3) d 199.8, 148.6, 140.8,
135.2, 131.7, 118.4, 110.0, 41.4, 33.2, 32.6, 26.6, 21.6, 15.2,
8.2; IR: (thin film) 1679 cm21. Anal. calcd for C14H16O2: C,
77.75; H, 7.53. Found: C, 77.45; H, 7.46.
1
mp 73–758C). H NMR (CDCl3) d 5.24 (s, 2H), 4.48 (t,
J¼2.1 Hz, 2H), 2.70 (m, 2H), 2.52 (m, 2H); 13C NMR
(CDCl3) d 200.6, 181.6, 114.3, 92.2, 62.5, 32.4, 26.2.
3.1.6. 2-(Hydroxymethyl)-3-(2-propenyl)-2-cyclopente-
none (13). To a solution of 2-bromopropene (4.1 g,
33.6 mmol) in THF (150 mL) at 2788C was added dropwise
tert-butyllithium (1.7 M in pentane, 39.5 mL, 67.2 mmol).
The solution was allowed to stir for 1 h. To this solution of
2-lithiopropene was added 12 (2.35 g, 16.8 mmol) in THF
(25 mL). The reaction mixture was stirred for 1.5 h at
2788C and then quenched with HCl (2 M, 20 mL). After
30 min, the aqueous layer was extracted with Et2O
(3£50 mL) and the combined organic phases were washed
with brine and was dried (MgSO4). After removal of
solvent, the residue was purified by flash column chroma-
tography on silica gel (100 g, hexanes/EtOAc, 3:1) to afford
13 (2.02 g, 78%) as a colorless oil: 1H NMR (CDCl3) d 5.30
(t, J¼1.2 Hz, 1H), 5.23 (s, 1H), 4.40 (d, J¼3.9 Hz, 2H), 3.26
(s, 1H), 2.68 (m, 2H), 2.43 (m, 2H) 2.00 (s, 3H); 13C NMR
(CDCl3) d 210.8, 171.5, 139.9, 137.7, 119.8, 55.6, 33.8,
28.6, 21.2; HRMS (FAB) calcd for C9H12O2 (Mþ)
152.0859. Found: 152.0831.
3.1.10. Ethyl 2-(2-hydroxylmethylcyclopent-2-enon-3-
yl)propionate (17). To a solution of ethyl propionate
(3.50 mL, 30 mmol) in anhydrous THF (20 mL) was added
LDA (0.5 M, 70 mL) at 2788C under nitrogen in 10 min.
After stirring for 30 min, 16 (3.00 g, 21.4 mmol) in
anhydrous THF (120 mL) was added dropwise in a period
of 1 h. The reaction mixture was warmed to room
temperature and then HCl (2 M, 16 mL) was added. The
solution was stirred for 30 min. The aqueous layer was
extracted with CH2Cl2 (3£30 mL), and the combined

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H.-K. Yim et al. / Tetrahedron 59 (2003) 1877–1884
organic phase was washed with brine and dried (MgSO4).
After removal of the solvent, the residue was purified by
flash column chromatography on silica gel (100 g, hexanes/
acetone, 3:1) to afford 17 (3.40 g, 75%) as a colorless oil: 1H
NMR (CDCl3) d 4.20 (s, 2H), 4.05 (q, J¼7.2 Hz, 2H), 3.91
(q, J¼7.2 Hz, 1H), 2.57 (m, 2H), 2.29 (m, 2H), 1.28 (d,
J¼7.2 Hz, 3H), 1.14 (t, J¼7.2 Hz, 3H); 13C NMR (CDCl3) d
209.3, 172.4, 171.6, 139.5, 61.0, 54.1, 40.4, 33.8, 26.2, 14.9,
13.7. Anal. calcd for C11H16O4: C, 62.25; H, 7.60. Found: C,
62.07; H, 7.74.
was purified by flash column chromatography on silica gel
(30 g, hexanes/EtOAc, 3:1) to afford 20 (160 mg, 88%) as a
viscous colorless oil. Compound 20 showed very complex
1H and 13C NMR spectra due to the presence of a pair of
diastereomers in the same ratio. 1H NMR (CDCl3) d 7.06 (a
pair of d, J¼1.2, 0.9 Hz, 1H), 7.01 (s, 1H), 4.63 (d,
J¼4.5 Hz, 1H), 4.12 (m, 2H), 3.59 (m, 1H), 3.22 (d,
J¼4.2 Hz, 2H), 2.51 (m, 3H), 1.93 (a pair of d, J¼1.2 Hz,
3H), 1.62 (m, 1H), 1.27 (m, 6H); 13C NMR (CDCl3) d 173.7,
140.0, 139.7, 139.6, 139.5, 138.8, 138.6, 137.8, 137.5,
122.6, 122.4, 120.0, 119.9, 78.8, 78.6, 60.6, 60.5, 38.8, 32.1,
29.3, 19.7, 15.5, 15.2, 14.1, 14.0, 7.9; IR: (thin film) 3531,
1724, 1250 cm21. Anal. calcd for C16H22O4: C, 69.04; H,
7.97. Found: C, 69.11; H, 7.99.
3.1.11. Ethyl 2-(2-bromomethylcyclopent-2-enon-3-
yl)propionate (18). To
a solution of 17 (3.50 g,
16.5 mmol) in anhydrous Et2O (50 mL) was added PBr3
(1.00 mL, 10.5 mmol) at 08C. After stirring for 30 min,
MeOH (5 mL) was added. The reaction mixture was stirred
for 10 min and then water was added. The aqueous layer
was separated and was extracted with Et2O (3£30 mL). The
combined organic phase was washed with brine and dried
(MgSO4). After removal of solvent, the residue was purified
by flash column chromatography on silica gel (80 g,
hexanes/acetone, 4:1) to afford 18 (4.50 g, 98%) as a pale
3.1.14. Ethyl[1-benzyloxy-2-(4-methylfuran-3-yl)-
methylcyclopent-2-ene-3-yl]propionate (21). To
a
solution of 20 (100 mg, 0.36 mmol) in anhydrous DMF
(5 mL) was added NaH (30 mg, 1.25 mmol). After stirring
for 20 min, to the mixture was added slowly benzyl bromide
(0.06 mL, 0.54 mmol). The solution was stirred for an
additional 2 h at room temperature. The solvent was
removed under reduced pressure and the residue was re-
dissolved in CH2Cl2 (30 mL). The organic phase was
washed with water (3£10 mL) and then was separated. After
removal of solvent, the residue was purified by flash column
chromatography on silica gel (30 g, hexanes/EtOAc, 10:1)
to afford 21 (120 mg, 92%) as a pale yellow oil. Compound
1
yellow oil: H NMR (CDCl3) d 4.04 (dq, J¼2.4, 7.2 Hz,
2H), 3.91 (s, 2H), 3.85 (q, J¼7.2 Hz, 1H), 2.52 (m, 2H),
2.29 (m, 2H), 1.29 (d, J¼7.2 Hz, 3H), 1.11 (t, J¼7.2 Hz,
3H); 13C NMR (CDCl3) d 205.6, 173.7, 170.8, 137.4, 61.0,
40.8, 33.4, 26.2, 18.1, 14.4, 13.6; HRMS (FAB) calcd for
C11H15BrO3 (MþH)þ 275.0277. Found: 275.0265.
1
21 showed very complex H and 13C NMR spectra due to
3.1.12. Ethyl [2-(4-methylfuran-3-yl)methylcyclopent-2-
enon-3-yl]propionate (19). To a solution of 18 (500 mg,
1.8 mmol) in anhydrous THF (10 mL) was added K3PO4
(2 M, 3 mL) and Pd(PPh3)4 (100 mg, 0.09 mmol). The
mixture was heated to 608C while 3 (200 mg, 0.7 mmol) in
THF (10 mL) was added dropwise in 30 min. The reaction
mixture was then refluxed for 2 h. After cooling down, the
mixture was filtered through a plug of glass wool and the
solids were washed with Et2O. The aqueous layer was
separated and was extracted with Et2O (3£20 mL). The
combined organic phase was washed with brine and dried
(MgSO4). After removal of solvent, the residue was purified
by flash column chromatography on silica gel (50 g,
hexanes/EtOAc, 8:1) to afford 19 (276 mg, 55%) as a pale
the presence of a pair of diastereomers in the same ratio. 1H
NMR (CDCl3) d 7.34 (m, 5H), 7.14 (d, J¼0.9 Hz, 1H), 7.04
(s, 1H), 5.10 (s, 1H), 4.53 (m, 2H), 4.37 (m, 1H), 4.10 (m,
1H), 3.70 (m, 1H), 3.23 (d, J¼3.9 Hz, 2H), 2.40 (m, 3H),
1.93 (m, 3H), 1.80 (m, 1H), 1.31 (m, 6H); 13C NMR
(CDCl3) d 173.8, 173.6, 140.3, 139.8, 139.4, 139.2, 139.1,
138.8, 128.4, 128.2, 128.0, 127.8, 127.7, 127.6, 127.4,
127.3, 122.6, 122.4, 119.7, 85.2, 85.1, 70.7, 70.0, 66.2, 60.5,
38.9, 30.0, 29.9, 29.6, 28.4, 28.3, 19.9, 15.7, 15.5, 15.3,
14.1, 8.0; IR: (thin film) 3096, 2982, 1720 cm21. Anal.
calcd for C23H28O4: C, 74.97; H, 7.66. Found: C, 74.72; H,
7.57.
3.1.15. 5-Benzyloxy-4,5,6,7,8-pentahydro-3,8-dimethyl-
azuleno[6,5-b]furan-9(4H)-one (22). To a solution of 21
(368 mg, 1 mmol) in MeOH (15 mL) was added slowly an
aqueous solution of NaOH (2 M, 5 mL). The mixture was
then refluxed for 10 h. After that water (10 mL) was added
and the resulting mixture was washed with CH2Cl2 (10 mL).
The aqueous layer was acidified with HCl (3N) until the pH
reached 1. It was then extracted with CH2Cl2 (5£10 mL).
The combined organic extract was dried (MgSO4) and
evaporated under reduced pressure. The residue was
redissolved in anhydrous CH2Cl2 (20 mL). Trifluoroacetic
anhydride (0.4 mL, 3.2 mmol) was slowly added. After
stirring at 08C for 6 h, saturated NaHCO3 solution (15 mL)
was added. The mixture was allowed to stir for a further 1 h,
the organic layer was separated and the aqueous layer was
extracted with CH2Cl2 (3£20 mL). The combined organic
extract was dried (MgSO4) and evaporated. The residue was
purified by flash column chromatography on silica gel (30 g,
hexanes/EtOAc, 8:1) to afford 22 (113 mg, 35%) as a
1
yellow oil: H NMR (CDCl3) d 7.02 (s, 1H), 6.93 (s, 1H),
4.06 (dq, J¼2.4, 7.2 Hz, 2H), 3.83 (q, J¼7.2 Hz, 1H), 3.19
(d, J¼1.2 Hz, 2H), 2.54 (m, 2H), 2.37 (m, 2H), 1.85 (d,
J¼0.9 Hz, 3H), 1.25 (d, J¼7.2 Hz, 3H), 1.15 (t, J¼7.2 Hz,
3H); 13C NMR (CDCl3) d 208.2, 171.7, 170.4, 139.4, 139.3,
139.1, 121.9, 119.5, 60.9, 40.5, 33.6, 25.6, 16.8, 14.8, 13.7,
7.7; IR: (thin film) 1735, 1680 cm21. Anal. calcd for
C16H20O4: C, 69.55; H, 7.29. Found: C, 69.31; H, 7.40.
3.1.13. Ethyl [1-hydroxy-2-(4-methylfuran-3-yl)methyl-
cyclopent-2-en-3-yl]propionate (20). To a solution of 19
(180 mg, 0.65 mmol) in dry MeOH (10 mL) was added
CeCl3 (162 mg, 0.65 mmol). To this solution was added
NaBH4 (130 mg, 3.3 mmol). After stirring for 30 min, the
reaction mixture was quenched with acetone. The solvent
was removed under reduced pressure and the residue was
re-dissolved in CH2Cl2 (20 mL). Water (5 mL) was added
and the aqueous layer was separated and was extracted with
CH2Cl2 (3£10 mL) and the combined organic phase was
dried (MgSO4). After removal of the solvent, the residue
1
colorless oil. Compound 22 showed very complex H and
13C NMR spectra due to the presence of a pair of

H.-K. Yim et al. / Tetrahedron 59 (2003) 1877–1884
1883
1
diastereomers in the same ratio. H NMR (CDCl3) d 7.34
(m, 5H), 6.96 (s, 1H), 4.53 (d, J¼12 Hz, 1H), 4.45 (bs, 1H),
4.37 (d, J¼12 Hz, 1H), 3.70 (m, 1H), 3.22 (s, 2H), 2.57 (bs,
1H), 2.28 (m, 1H), 2.14 (m, 1H), 1.93 (s, 3H), 1.86 (m, 1H),
1.30 (a pair of d, J¼7.2 Hz, 3H); 13C NMR (CDCl3) d 189.1,
147.1, 142.3, 138.7, 138.4, 137.3, 137.2, 137.0, 131.7,
130.4, 128.3, 127.7, 127.5, 122.2, 120.1, 85.2, 70.8, 38.4,
31.4, 29.8, 29.6, 27.3, 27.0, 23.0, 7.9. Anal. calcd for
C21H22O3: C, 78.23; H, 6.88. Found: C, 78.13; H, 6.92.
28.3, 25.6, 25.2, 23.0, 8.4; IR: (thin film) 3084, 2950 cm21
.
Anal. calcd for C21H24O2: C, 81.78; H, 7.84. Found: C,
81.77; H, 7.75.
3.1.18. 4,4a,5,6,7,9-Hexahydro-5-hydroxy-3,8-dimethyl-
azuleno[6,5-b]furan (25). To a solution of 24 (31 mg,
0.1 mmol) in CH2Cl2 (3 mL) was added slowly BBr3
(1.0 M, 0.15 mL) at 2788C. The reaction mixture was
stirred at 2788C for 2 h, then stirred for another 30 min at
room temperature. After that, the solution was again cooled
to 2788C and was added MeOH (1 mL). The mixture was
allowed to stir for a further 1 h. After removal of solvent, the
residue was purified by flash column chromatography on
silica gel (10 g, hexanes/EtOAc, 5:1) to afford 25 (14.6 mg,
67%) as a viscous colorless oil. Compound 25 showed very
complex 1H and 13C NMR spectra due to the presence of a
pair of diastereomers in the same ratio. 1H NMR (CDCl3) d
6.97 (s, 1H), 3.83 (m, 1H), 3.63 (m, 1H), 3.03 (bm, 1H), 2.78
(m, 1H) 2.54 (m, 2H), 2.42 (m, 4H), 1.95 (a pair of d,
J¼1.2 Hz, 3H), 1.71 (a pair of s, 3H); 13C NMR (CDCl3) d
148.2, 138.5, 138.3, 138.2, 135.2, 135.0, 122.4, 122.1,
117.7, 117.5, 79.9, 51.8, 38.2, 28.5, 28.3, 26.6, 25.6, 25.4,
23.9, 8.2; IR: (thin film) 3497, 1672 cm21. Anal. calcd for
C14H18O2: C, 77.03; H, 8.31. Found: C, 77.18; H, 8.03.
3.1.16. 5-Benzyloxy-4,4a,5,6,7-pentahydro-3,8-dimethyl-
azuleno[6,5-b]furan-9(4H)-one (23). To a stirred solution
of 22 (32 mg, 0.1 mmol) in CH2Cl2 (1 mL) was added DBU
(0.04 mL, 0.25 mmol) at 2788C. After being stirred for 30 h
at 2788C, the reaction mixture was quenched by the
addition of 1N HCl, and Et2O was then added. The organic
layer was separated, washed with brine, and the solvent
were removed under reduced pressure. The residue was
purified by flash column chromatography on silica gel
containing 5% AgNO3 (10 g, hexanes/Et2O, 15:1) to afford
23 (21 mg, 65%) as a colorless oil. Compound 23 showed
very complex 1H and 13C NMR spectra due to the presence
of a pair of diastereomers in the same ratio. 1H NMR
(CDCl3) d 7.32 (m, 5H), 7.04 (s, 1H), 4.63 (d, J¼12 Hz,
1H), 4.42 (d, J¼12 Hz, 1H), 2.72 (m, 2H), 2.47 (m, 2H),
2.04 (m, 2H), 1.95 (s, 3H), 1.86 (m, 2H), 1.74 (a pair of s,
3H); 13C NMR (CDCl3) d 178.8, 150.8, 147.3, 142.3, 137.8,
137.6, 128.4 127.8, 127.6, 126.4, 126.3, 122.7, 84.4, 73.2,
49.2, 37.7, 29.3, 29.2, 23.0, 22.3, 8.2. Anal. calcd for
C21H22O3: C, 78.23; H, 6.88. Found: C, 78.28; H, 6.79.
3.1.19. 4,4a,6,7,9-Pentahydro-3,8-dimethylazuleno[6,5-
b]furan-5(4H)-one (26). To a solution of 25 (24 mg,
0.11 mmol) in anhydrous CH2Cl2 (2 mL) was added
IBX18 (76 mg 0.27 mmol) at room temperature. After
being stirred for 2 h, the white solids were filtered and
washed with CH2Cl2. The solvent was removed under
reduced pressure, the residue was purified by flash column
chromatography on silica gel (10 g, hexanes/EtOAc, 8:1) to
afford 26 (17 mg, 72%) as a viscous colorless oil. 1H NMR
(CDCl3) d 7.00 (s, 1H), 3.65 (d, J¼18 Hz, 1H), 3.42 (dd,
J¼13.2, 3.6 Hz, 1H), 2.98 (d, J¼18 Hz, 1H), 2.83 (m, 2H),
2.49 (m, 2H), 2.24 (m, 2H), 1.95 (s, 3H), 1.75 (s, 3H); 13C
NMR (CDCl3) d 206.2, 146.4, 136.2, 135.1, 125.7, 121.7,
116.9, 60.3, 40.8, 33.6, 30.5, 29.3, 19.7, 8.4; HRMS (FAB)
calcd for C14H16O2 (MþH)þ 217.1215. Found: 217.1223.
3.1.17. 5-Benzyloxy-4,4a,5,6,7,9-hexahydro-3,8-dimethyl-
azuleno[6,5-b]furan (24). To a solution of 23 (32 mg,
0.1 mmol) in dry MeOH (2 mL) was added CeCl3 (25 mg,
0.1 mmol). To this solution was added NaBH4 (10 mg,
0.2 mmol) at 08C. After stirring for 30 min, the reaction
mixture was quenched with acetone. The solvent was
removed under reduced pressure and residue was re-
dissolved in CH2Cl2 (5 mL), and water (2 mL) was added.
The aqueous layer was separated and was extracted with
CH2Cl2 (3£5 mL) and the combined organic phase was
dried (MgSO4). After removal of solvent, the residue was
further dried in vacuo. It was then re-dissolved in CH2Cl2
(5 mL). To this solution was added Et3N (0.1 mL) and MsCl
(0.01 mL) at 08C. After being stirred for 12 h, Et3N and
MsCl were removed in vacuo, and the residue was re-
dissolved in anhydrous Et2O (5 mL). To this solution was
added lithium aluminum hydride (10 mg) and the reaction
mixture was allowed to reflux for 1 day. After that water
(2 mL) was added and the aqueous layer was extracted with
Et2O (3£5 mL). The combined organic phase was washed
with brine (3 mL). After removal of solvent, the residue was
purified by flash column chromatography on silica gel (10 g,
hexanes/Et2O, 20:1) to afford 24 (11.6 mg, 38%) as a pale
3.1.20. (6)-Echinofuran (1). To a solution of [(trimethyl-
silyl)methyl]magnesium chloride [prepared from Mg
(7.2 mg, 0.296 mmol) and (chloromethyl)trimethylsilane
(36.4 mg, 0.3 mmol)] in anhydrous Et2O (2 mL) was
added dropwise a solution of 26 (24.6 mg, 0.1 mmol) in
Et2O (1 mL) at room temperature, and stirring was
continued for 1 h at the same temperature. The reaction
mixuture was poured into saturated NH4Cl solution, and
extracted with Et2O (3£5 mL). The combined extracts were
washed with brine and dried (MgSO4). The residue resulting
from the evaporation of the solvent was dissolved in THF
(3 mL). To this solution was added NaH (8 mg, 0.33 mmol)
under stirring. After refluxing had been continued for 6 h,
the reaction mixture was poured into saturated aqueous
NH4Cl solution and extracted with Et2O (3£5 mL). After
removal of solvent, the residue was purified by flash column
chromatography on silica gel (5 g, hexanes/EtOAc, 40:1) to
afford 1 (9.7 mg, 40%) as a pale yellow oil which darkened
on standing. 1H NMR (CDCl3) d 6.98 (s, 1H), 4.96 (s, 1H),
4.89 (s, 1H), 3.70 (d, J¼18 Hz, 1H), 3.34 (d, J¼12 Hz, 1H),
2.98 (d, J¼18 Hz, 1H), 2.52 (m, 2H), 2.47 (m, 2H), 2.29 (m,
2H), 1.85 (s, 3H), 1.77 (s, 3H); 13C NMR (75 MHz, CDCl3)
yellow oil. Compound 24 showed very complex 1H and 13
C
NMR spectra due to the presence of a pair of diastereomers
in the same ratio. 1H NMR (CDCl3) d 7.35 (m, 5H), 6.97 (s,
1H), 4.58 (d, J¼12 Hz, 1H), 4.42 (d, J¼12 Hz, 1H), 3.70
(m, 1H), 3.13 (m, 1H), 2.86 (m, 2H) 2.54 (m, 2H), 2.24 (m,
2H), 1.92 (a pair of d, J¼0.9 Hz, 3H), 1.85 (m, 2H), 1.74 (a
pair of s, 3H); 13C NMR (CDCl3) d 146.6, 140.8, 137.6,
137.2, 137.0, 135.2, 135.0, 128.3, 127.8, 127.6, 121.7,
121.5, 117.2, 84.4, 84.3, 73.9, 73.8, 49.4, 36.4, 36.2, 33.6,

1884
H.-K. Yim et al. / Tetrahedron 59 (2003) 1877–1884
Appl. Chem. 1996, 68, 723–726. (c) Ye, X.-S.; Yu, P.; Wong,
H. N. C. Liebigs Ann. Chem. 1997, 458–459.
d 157.3, 148.5, 140.8, 135.9, 125.2, 121.3, 118.7, 105.9,
46.3, 34.0, 33.2, 30.6, 30.1, 22.2, 8.6. MS (EI) m/z (%) [M]þ
214 (100), 157 (18), 109 (38), 91 (25).
7. Tanis, S. P.; Robinson, E. D.; McMills, M. C.; Watt, W. J. Am.
Chem. Soc. 1992, 114, 8349–8362.
8. Schultz, A. G.; Motyka, L. A.; Plummer, M. J. Am. Chem. Soc.
1986, 108, 1056–1064.
Acknowledgements
9. Miyaura, N.; Yanagi, T.; Suzuki, A. Synth. Commun. 1981, 11,
513–519.
The work described in this paper was supported by a grant
from the Research Grants Council of the Hong Kong SAR,
China (Project No. CUHK 4178/97P) and the Area of
Excellence Scheme established under the University Grants
Committee of the Hong Kong SAR, China (Project No.
Aoe/P-10/01).
10. For examples of related references, see: (a) Martin, A.; Yang,
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11. Yick, C.-Y.; Wong, H. N. C. Tetrahedron 2001, 57,
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