Synthetic studies towards furosesquiterpenoids: Total synthesis of (±) desmethylpallescensin-A, (±) isopallescensin-A and (±) isopallescensin-1

Article abstract of DOI:10.1016/j.tet.2004.01.068

A new approach for a short and efficient synthesis of common cyclohexenone intermediate towards the total synthesis of some furosesquiterpenes and their analogues are described. Regioselective alkylation of Hagemann's ester with 2/3-furyl-2-ethyl bromide followed by hydrolysis cum in situ decarboxylation and 1,4-addition with Gilman's reagent produced the cyclohexanone derivatives which have been utilized for total synthesis of (±) isopallescensin-A, (±) 10-desmethylpallescensin-A, (±) 5-desmethyl-4,5- dehydromicrocionin-1 and (±) isopallescensin-1.

Full text of DOI:10.1016/j.tet.2004.01.068

Tetrahedron 60 (2004) 2805–2811
Synthetic studies towards furosesquiterpenoids: total synthesis of
(6) desmethylpallescensin-A, (6) isopallescensin-A and
(6) isopallescensin-1
*
Sajal Kanti Mal, Gandhi K. Kar and Jayanta K. Ray
Department of Chemistry, Indian Institute of Technology, Kharagpur 721302, India
Received 20 October 2003; revised 24 December 2003; accepted 22 January 2004
Abstract—A new approach for a short and efficient synthesis of common cyclohexenone intermediate towards the total synthesis of some
furosesquiterpenes and their analogues are described. Regioselective alkylation of Hagemann’s ester with 2/3-furyl-2-ethyl bromide
followed by hydrolysis cum in situ decarboxylation and 1,4-addition with Gilman’s reagent produced the cyclohexanone derivatives which
have been utilized for total synthesis of (^) isopallescensin-A, (^) 10-desmethylpallescensin-A, (^) 5-desmethyl-4,5-dehydromicrocionin-
1 and (^) isopallescensin-1.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
bioactive furosesquiterpenes, we have developed a method
for constructing a tricyclic framework using acid catalysed
cyclisation reactions leading to tricyclic sesquiterpenoids
and we sought to prepare a range of model compounds.
These are shown in Figure 1.
Furoterpenes have been found to occur abundantly in nature
particularly in higher plants and marine organism. The
biological activity associated with a number of drimane
metabolites1 specially furosesquiterpenes has stimulated
considerable interest in their synthesis.2 Among the broad
structural variety of these natural furosesquiterpenes occupy
a special place.3 Most of these natural products have
attracted much interest due to their inherent biological
properties.4 Synthesis of such furoterpenes are a challenging
problem for many research laboratories even today. These
includes compounds like Pallescensin A-G,5 Pallescensin
1-3,5 Microcionin,5 Spiniferin5 and several other furano-
sesquiterpenes. A large number of syntheses6a–m of several
furoterpenes with complex structures have come out in last
few decades and many more are still coming out. This
attracted us to study the synthesis of various furoterpenes
and our aim is to achieve the synthesis of such compounds
via a common intermediate. One such common intermediate
for the synthesis of compound 2-9 may be suitably
substituted cyclohexenone derivatives (1), which in turn
can easily be obtained from Hagemann’s ester (Fig. 1).
In earlier synthesis of tricyclic furanosesquiterpenoids, most
of the synthesis describes the linear approaches that
sequentially build the tricyclic skeleton from C ring
precursor or AB ring precursor to ABC tricyclic framework.
In our present approach we have utilized a common AC ring
precursor 2-(2-furyn-3-yl-ethyl)-3-methyl cyclohex-2-
enone (1) (X¼H) for constructing ABC tricyclic framework
(Fig. 2).
2. Results and discussion
The model study in this connection was performed with
2-furyl analogue as in Scheme 1 to achieve the synthesis of
(^) isopallaescensin-A and (^) isopallescensin-1.
Employing our experience8 in the synthesis of regio-
specifically substituted furan we targeted to expand our
protocol towards the synthesis of furosesquiterpenes
through a common intermediate (1). In this connection we
wish to report our approach towards the synthesis of such
furoterpenes and their analogues via common intermediate
2-(2-furan-3-yl-ethyl)-3-methyl-cyclohex-2-enone (1)
(X¼H) and its 2-furyl analogues (12) respectively. Thus
the Hagemann’s ester (10) on regioselective alkylation with
The construction of a carbocyclic framework, especially one
with a quaternary center, is key to the rapid and efficient
synthesis of many natural products.7 As part of our current
research programme towards the synthesis of potentially
Keywords: Hagemann’s ester; Alkylation; Furoterpenes; Conjugate
addition; Cyclisation; Isopallescensis-A; Desmethyl pallescensin-A.
*
Corresponding author. Tel.: þ913222283326; fax: þ913222282252;
t
e-mail address: jkray@chem.iitkgp.ernet.in
2-(2-furyl-ethyl bromide)/tBuOK in BuOH under reflux
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.01.068

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S. K. Mal et al. / Tetrahedron 60 (2004) 2805–2811
Figure 1.
afforded compound (11) as viscous yellow oil in 65% yield.
Hydrolysis of (11) with KOH/EtOH–H2O furnished 2-(2-
furan-2-yl-ethyl)-3-methyl cyclohex-2-enone (12) in 51%
yield in inert atmosphere. Conjugate addition to the a,b
unsaturated ketone (12) with CH3MgI/CuI met with failure.
However, compound (13) was successfully synthesized in
good yield from the cyclohexenone derivative (12) using
Gilman’s reagent (Me2CuLi) in combination with
BF3:Et2O.9 The ketone (13) when treated with MeLi/or
MeMgI in ether at 230 8C furnished the desired cyclo-
hexanol derivative. Attempts to cyclise the cyclohexanol
derivatives with BF3:Et2O or Poly Phosphoric Acid (PPA) met
with failure. However, this compound was successfully
cyclised with the help of a mixture of anhydrous HCO2H and
cyclohexane to produce a mixture of (^) isopallescensin-A
Figure 2.
Scheme 1. Reagents and conditions: (All the reactions were carried out under argon atm) (i) tBuOK, 2-(2-furyl-ethyl bromide), reflux, 12 h (ii) KOH, EtOH–
H2O, reflux for 8 h (iii) Me2CuLi, BF3:Et2O, ether, 250 8C (15 min), then 230 8C (1 h) (iv) MeLi, ether, 230 8C (1 h) (v) Anh. HCOOH, cyclohexane, rt,
30 min (vi) (CF3CO)2O, CF3COOH, rt, 8 h.

S. K. Mal et al. / Tetrahedron 60 (2004) 2805–2811
2807
However, when this cyclohexenone derivative (1) (X¼H)
was treated with the Me2CuLi/BF3:Et2O furnished no 2-(2-
furan-3-yl-ethyl)-3,3-dimethyl cyclohexanone (20) as
expected but disappointingly it directly formed the tricyclic
product (21) (61%), possibly through nucleophilic attack on
the intermediate ketone (20) formed, by the activated furan
moiety, followed by Lewis acid catalysed dehydration of the
resulting tert-alcohol. We next surveyed the possibility of
transforming 21 into compound 22 by hydrogenation over
5% palladium on carbon in different solvent systems. The
most suitable solvent systems composed of ethyl acetate,
ethanol, diethyl amine (1:1:0.2). In order to stop over
reduction, the progress of the reaction was arrested before
full conversion, furnished (^) 10-desmethylpallescensin-A
(22) as a major isolable product in 46% yield. The trans-
geometry was confirmed by 2D 1H spectra and as well as by
analogy Scheme 4.6i
Scheme 2. Reagents and conditions: Ph3PCH3I/n-BuLi; THF, 230 8C to rt,
3 h (N2 atmosphere).
(15) and (^) isopallescensin-1 (16) (in the ratio 3:2) as
colourless oil and the structures were confirmed from their
1H and 13C NMR spectra. The trans-stereochemistry of the
A/B ring junction of compound (15) was assigned from the
chemical shift value for the gem-dimethyl at C-4 and
angular methyl group at C-10 (which appeared at d 0.91,
0.94 and 1.14 ppm, respectively) as well as by analogy.10
Attempt to cyclise with the help of a mixture of
trifluoroacetic anhydride in trifluoroacetic acid led to the
formation of the trifluoroacetyl derivatives (17) of iso-
pallescensin-A (15) in 38% yield.
1,2-Addition reaction of the cyclohexenone derivative (1)
with MeLi in ether also furnished no isolable cyclohexanol
derivative. In this case also the cyclohexanol derivative
undergoes rapid cyclisation to produce (^) 5-desmethyl-
4,5-dehydromicrocionin-1 (23) as the only isolable product
from the reaction mixture. The crude product was identical
with the product obtained after column purification. All
these compounds have been characterized by the usual
spectroscopic method (IR, 1H NMR, 13C NMR, Mass
spectra) as well as elemental analysis.
Wittig olefination of the ketone (13) with the ylide
Ph3PvCH2 resulted in the formation of 1,2-dihydro
isopallescensin-2 (18) in 71% yield Scheme 2.
Thus the method showed the potential for the entry to the
synthesis of many sesquiterpenoids via suitable furyl-ethyl
cyclohexenone derivatives as common intermediates.
Being inspired with these results we then directed our efforts
to apply this methodology for the synthesis of various
natural pallescensins from the cyclohexenone derivative (1)
(X¼H). Compound 1 was prepared from Hagemann’s ester
(10) and 2-(3-furyl) ethyl bromide following a two steps
procedure as used for the synthesis of compound 19
Scheme 3.
In summary, the present study has established the feasibility
of preparing the common intermediates by a very con-
venient method based on alkylation of Hagemann’s ester
with furyl-ethyl bromide to generate 2-(2/3-furan-2-yl-
ethyl)-3-methylcyclohex-2-enone derivative as a common
intermediate which can be exploited as a gateway to several
tricyclic furoterpenes and their analogues.
Scheme 3. Reagents and conditions: (All the reactions were carried under argon atm) (i) tBuOK, 2-(3-furyl-ethyl bromide), reflux, 12 h (ii) KOH, EtOH–H2O,
reflux for 8 h.
Scheme 4. Reagents and conditions: (i) Me2CuLi–BF3:Et2O, ether, 250 8C (15 min), then 230 8C (1 h) (ii) H2/5% Pd–C (iii) MeLi, ether, 230 8C to rt.

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S. K. Mal et al. / Tetrahedron 60 (2004) 2805–2811
3. Experimental
(–CH), 151.26, 155.19, 172.13, 197.35; MS (EI, 70 eV)
m/z 276 (Mþ), 203, 182, 123, 67. Anal. calcd for C16H20O4:
C, 69.55; H, 7.30. Found: C, 69.74; H, 7.23.
3.1. General information
The compounds described are all racemates. All reagents
and solvents were reagent grade. Further purification and
drying by standard methods were employed in each step. All
organic solvents were evaporated under reduced pressure
with a rotary evaporator. The plates used for thin-layer
chromatography (TLC) were E. Merck silicagel 60F254
(0.25 mm thickness) precoated on aluminum plates, and
they were visualized under short (254 nm) UV light.
Column chromatography was performed using silica gel
(60–120 mesh and 230–400 mesh for flash chromato-
graphy, SRL) and neutral alumina. NMR spectra were
3.1.2. 2-(2-Furan-2-yl-ethyl)-3-methyl-cyclohex-2-enone
(12). A solution of KOH (3.25 g, 58.03 mmol) in 12 mL
water and 12 mL ethanol was added to the ketoester (11)
(4 g, 14.49 mmol). The reaction mixture was refluxed with
stirring under N2 atmosphere for 8 h. Excess alcohol was
then removed by distillation under reduced pressure and the
residue was diluted with ice water, acidified with 6 N HCl,
and extracted with ether (4£50 mL). The ether extract was
washed successively with brine solution, 5% NaHCO3
solution, and water and then dried (Na2SO4). Removal of
the solvent gave the title compound, which was purified by
column chromatography (silica gel, pet ether–ethyl acetate;
7:3).
1
recorded on a Bruker spectrometer (200 MHz for H and
50 MHz for 13C). All NMR measurements were carried out
˚
at 300 K in deuterated chloroform solution (dried with 4 A
molecular sieves) unless otherwise stated. Chemical shifts
are reported as parts per million (ppm) in d unit in the scale
Yellow oil (1.5 g, 51%); IR (CHCl3): n 1661 (CvO) cm21
;
1H NMR (CDCl3, 200 MHz) d 1.75 (s, 3H, methyl protons),
1.86–1.96 (m, 2H), 2.25–2.39 (m, 4H), 2.58–2.63 (m, 4H),
5.90 (d, 1H, J¼3.16 Hz, furan b proton), 6.23–6.25 (m, 1H,
furan b proton), 7.27 (d, 1H, J¼1.8 Hz, furan a proton); 13C
NMR (CDCl3, 50 MHz) d 20.77 (CH3), 22.17 (CH2), 25.47
(CH2), 27.73 (CH2), 32.79 (CH2), 38.12 (CH2), 105.17
(–CH), 110.12 (–CH), 134.09, 140.65 (–CH), 155.62,
156.47, 198.55; MS (EI, 70 eV) m/z 204 (Mþ), 136, 123,
104, 89, 67. Anal. calcd for C13H16O2: C, 76.44; H, 7.90.
Found: C, 76.32; H, 7.72.
1
relative to the resonance of CDCl3 (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
abbreviation: s, singlet; d, doublet; t, triplet; q, quartet; m,
1
multiplet; brs, broad singlet; brd, broad doublet. H NMR
data are reported in this order: chemical shift; multiplicity,
number of proton, coupling constant(s). IR spectra were
recorded on a Parkin–Elmer 830 machine. Mass spectra
were obtained from IICB, Kolkata and determined at an
ionized voltage of 70 eV. Relevant data were tabulated as
m/z. Elemental analyses were performed at CDRI,
Lucknow.
3.1.3. 2-(2-Furan-2-yl-ethyl)-3,3-dimethyl-cyclohexa-
none (13). To a stirred suspension of CuI (1.40 g,
7.35 mmol) in dry ether (5 mL) under N2 at 225 8C (bath
temperature) was added MeLi in ether (1.3 M) (11.2 mL,
14.55 mmol). The resulting yellow suspension was cooled
to 250 8C and BF3:Et2O (0.93 mL, 7.33 mmol) was added.
After 20 min the cyclohexanone (0.5 g, 2.45 mmol) in Et2O
(5 mL) was added dropwise (15 min) and the mixture was
stirred at 230 8C for 15 min. An additional lot of BF3:Et2O
(0.93 mL, 7.33 mmol) was added and stirring was continued
at 230 8C for 1 h and then allowed to 0 8C. Quench it with
aqueous NH4Cl and extracted with ether (3£50 mL). The
ether extract was washed successively with ice water and
then dried (Na2SO4). Removal of the solvent gave the title
compound, which was purified by column chromatography
(silica gel, pet ether–ethyl acetate 8:2).
3.1.1. 3-(2-Furan-2-yl-ethyl)-2-methyl-4-oxo-cyclohex-2-
enecarboxylic acid ethyl ester (11). Potassium (1.07 g,
27.44 mmol) was dissolved in dry tert-butyl alcohol
(20 mL) and then the latter was distilled off until a white
solid appeared. This was cooled to room temperature (rt)
and
2-methyl-4-oxocyclohex-2-ene
carboxylate
(Hagemann’s ester) (10) (5 g, 27.47 mmol) was added in
one portion with stirring under N2 atmosphere. The red
solution so formed turned into straw-yellow solid a few
minutes after the addition. 2-Furyl ethyl bromide (4.8 g,
27.43 mmol) was then added and the resultant solution
refluxed with stirring for 12 h. The cooled reaction mixture
was then poured onto crushed ice, acidified with cold HCl
(6 N) and extracted with ether (3£100 mL). The ether
solution was washed thoroughly with water and dried
(Na2SO4). Evaporation of the solvent afforded a yellow
liquid which was purified by reduced pressure distillation.
Sweet smelling yellow oil (0.46 g, 85%); IR (CHCl3): n
1708 (CvO) cm21; 1H NMR (CDCl3, 200 MHz) d 0.75 (s,
3H), 1.01 (s, 3H), 1.59–2.5 (m, 8H), 2.6–2.65 (m, 3H), 5.95
(d, 1H, J¼3.04 Hz), 6.25 (brs, 1H), 7.28 (d, 1H, J¼1.7 Hz);
13C NMR (CDCl3, 50 MHz) d 21.44 (CH3), 22.11 (CH2),
22.89 (CH2), 25.27, 26.70 (CH2), 29.20 (CH3), 39.22 (CH2),
41.19 (CH2), 59.48 (–CH), 104.78 (–CH), 109.77 (–CH),
140.54 (–CH), 155.64, 212.97; MS (EI, 70 eV) m/z 220
(Mþ), 126, 106, 88, 67. Anal. calcd for C14H20O2: C, 76.33;
H, 9.15. Found: C, 76.21; H, 8.95.
Faint yellow oil (4.9 g, 65%) (bp 140–142 8C/1 mm Hg);
1
IR (CHCl3): n 1662 (–CO2Et), 1725 (CvO) cm21; H
NMR (CDCl3, 200 MHz) d 1.27 (t, 3H, J¼7.1 Hz, methyl
protons), 1.8 (s, 3H, methyl protons), 2.00–2.61 (m, 4H),
2.66 (brs, 4H), 3.24 (brt, 1H, J¼4.8 Hz), 4.18 (q, 2H,
J¼7.1 Hz, methylene protons), 5.93 (d, 1H, J¼2.9 Hz, furan
b proton), 6.24 (dd, 1H, J¼2.9, 1.9 Hz, furan b proton), 7.27
(d, 1H, J¼1.9 Hz, furan a proton); 13C NMR (CDCl3,
50 MHz) d 14.01 (CH3), 19.97 (CH3), 24.41 (CH2), 25.44
(CH2), 26.74 (CH2), 34.17 (CH2), 47.59 (–CH), 61.13
(CH2), 105.37 (–CH), 110.15 (–CH), 135.97, 140.74
3.1.4. 2-(2-Furan-2-yl-ethyl)-1,3,3-trimethyl-cyclohexa-
nol (14). To a stirred solution of ketone (13) (0.3 g,
1.36 mmol) at 230 8C in dry ether (5 mL), an ethereal
solution of MeMgI [prepared from Mg turnings (0.035 g,
1.46 mmol), MeI (0.1 mL) in dry ether (5 mL)] or MeLi

S. K. Mal et al. / Tetrahedron 60 (2004) 2805–2811
2809
(1.3 M, 1.1 mL, 1.36 mmol) was added dropwise for
30 min. The mixture was stirred for an additional 1 h at
0–5 8C. After workup with ether, the cyclohexanol (14) was
obtained as yellow oil, which was purified by column
chromatography (silica gel, pet ether–ethyl acetate 1:1).
2H), 7.30 (s, 1H); 13C NMR (CDCl3, 50 MHz) d 18.39,
18.74, 21.28, 23.64, 25.02, 27.10, 33.18, 33.38, 34.66,
38.10, 41.78, 51.79, 113.81, 129.4, 152.5, 160.56, 192.5;
MS (EI, 70 eV) m/z 314 (Mþ), 299 (M215, Bþ), 271, 257,
245, 243, 231, 217, 178, 137, 121, 103, 89, 67. Anal. calcd
for C17H21F3O2: C, 64.96; H, 6.73. Found: C, 65.14; H, 6.65.
1
Yellow oil (0.22 g, 69%); IR (CHCl3): n 3380 cm21; H
NMR (CDCl3, 200 MHz) d 0.82 (s, 3H), 0.96 (s, 3H), 1.16
(s, 3H), 1.44–1.69 (m, 8H), 2.62–2.75 (m, 4H), 5.99 (d, 1H,
J¼2.9 Hz), 6.27 (brs, 1H), 7.29 (d, 1H, J¼1.6 Hz); 13C
NMR (CDCl3, 50 MHz) d 18.23, 21.36, 24.37, 29.67, 30.25,
31.84, 34.70, 41.16, 41.73, 53.34, 65.80, 104.63, 110.01,
140.68, 156.20. MS (EI, 70 eV) m/z 236 (Mþ), 221, 219, 81,
67. Anal. calcd for C15H24O2: C, 76.23; H, 10.24. Found: C,
76.34; H, 10.11.
3.1.8. 2-[2-(2,2-Dimethyl-6-methylene-cyclohexyl)-
ethyl]furan (18). A 1.6 M solution of n-butyllithium
(1.0 mL, 1.6 mmol) was injected slowly to a cold
(230 8C) stirred suspension of methyltriphenylphos-
phonium iodide (0.65 g, 1.60 mmol) in dry THF (2.5 mL),
under argon atmosphere. After 2.5 h a THF solution of
(0.5 mL) of the cyclohexanone (13) (0.1 g, 0.46 mmol) was
injected dropwise. The stirring was continued at 230 8C for
about 30 min and then allowed to attain rt. It was further
stirred at rt (3–3.5 h) before quenching with ice water. The
THF was removed in rotary evaporator under reduced
pressure. Extraction with ether (3£25 mL) followed by the
usual work up afforded the crude product which was purified
by column chromatography (Neutral alumina/benzene–pet
ether, 1:5).
3.1.5. 6,6,9a-Trimethyl-4,5,5a,6,7,8,9,9a-octahydro-
naphtho[2,1-b]furan (15). Alcohol (14) (0.1 g,
0.42 mmol) was dissolved in cyclohexane (1.5 mL), and
formic acid (100%) (0.1 mL) was added. The mixture was
stirred vigorously for 1 h at rt under inert atmosphere. The
upper layer of the two phase system was yellow to brown in
colour, the bottom layer was dark purple. Ice water (5 mL)
was added, the aqueous layer was extracted with ether
(2£25 mL). The combined extracts were washed with 5%
NaHCO3 solution and brine. Solvent removed and the crude
products were purified by flash chromatography (200–400
mesh, pet ether).
Colourless oil (70 mg, 71%); IR (CHCl3): n 1635,
1
1602 cm21; H NMR (CDCl3, 200 MHz) d 0.89 (s, 3H),
0.94 (s, 3H), 1.4–2.2 (m, 8H), 2.41–2.65 (m, 3H), 4.56 (brs,
1H), 4.8 (brs, 1H), 5.95 (d, 1H, J¼3.0 Hz), 6.28 (dd, 1H,
J¼3.0, 1.8 Hz), 7.27 (brs, 1H); 13C NMR (CDCl3, 50 MHz)
d 23.56, 24.76, 26.28, 26.57, 28.29, 32.22, 36.01, 39.20,
53.43, 104.41, 107.61, 109.30, 140.57, 155.32, 156.14; MS
(EI, 70 eV) m/z 218 (Mþ), 203, 121, 67. Anal. calcd for
C15H22O: C, 82.52; H, 10.16. Found: C, 82.62; H, 10.10.
Colourless oil (36 mg, 40% [this is mixture of two isomers
which was separated using preparative thin-layer chromato-
graphic technique, elution with hexane]); IR (CHCl3): 2928,
1496, 1435, 1295, 740 cm21; 1H NMR (CDCl3, 200 MHz) d
0.91 (s, 3H), 0.94 (s, 3H), 1.14 (s, 3H), 1.38–1.90 (m, 8H),
2.54–2.69 (m, 3H), 6.15 (d, 1H, J¼1.9 Hz), 7.17 (d, 1H,
J¼1.8 Hz); 13C NMR (CDCl3, 50 MHz) d 18.89, 21.16,
22.63, 23.26, 24.33, 27.39, 34.19, 38.22, 41.97, 48.49,
53.43, 109.92, 120.25, 140.56, 156.61. Anal. calcd for
C15H22O: C, 82.52; H, 10.16. Found: C, 82.76; H, 9.96.
3.1.9. 3-(2-Furan-3-yl-ethyl)-2-methyl-4-oxo-cyclohex-2-
enecarboxylic acid ethyl ester (19). Potassium (0.64 g,
16.41 mmol) was dissolved in dry tert butyl alcohol (12 mL)
and then the latter was distilled off until a white solid
appeared. This was cooled to rt and 2-methyl-4-oxocyclo-
hex-2-ene carboxylate (Hagemann’s ester) (10) (3 g,
16.48 mmol) was added in one portion with stirring under
N2 atmosphere. The red solution so formed turned into
straw-yellow solid a few minutes after the addition. 3-furyl
ethyl bromide (2.9 g, 16.57 mmol) was then added and the
resultant solution refluxed with stirring for 12 h. The cooled
reaction mixture was then poured onto crushed ice, acidified
with cold HCl (6 N) and extracted with ether (3£100 mL).
The ether solution was washed thoroughly with water and
dried (Na2SO4). Evaporation of the solvent afforded a
yellow liquid which was purified by reduced pressure
distillation.
3.1.6. 2-[2-(2,6,6-Trimethyl-cyclohex-2-enyl)-ethyl]-
1
furan (16). Colourless oil; H NMR (CDCl3, 200 MHz) d
0.87 (s, 3H), 1.02 (s, 3H), 1.47 (s, 3H), 1.6–1.7 (m, 4H),
1.93–1.97 (m, 2H), 2.36–2.7 (m, 4H), 5.96 (brs, 1H, vinylic
proton), 6.26 (brs, 1H), 7.28 (brs, 1H). Anal. calcd for
C15H22O: C, 82.52; H, 10.16. Found: C, 82.84; H, 9.98.
3.1.7. 2,2,2-Trifluoro-1-(6,6,9a-trimethyl-4,5,5a,6,
7,8,9,9a-octahydro-naphtho[2,1-b] furan-2-yl)-ethanone
(17). A mixture of cyclohexanol (14) (50 mg, 0.21 mmol),
trifluoroacetic anhydride (2 mL), and trifluoroacetic acid
(0.5 mL) was stirred for 8 h at rt under argon atmosphere.
The brown mixture was then poured onto crushed ice and
extracted with ether (3£25 mL). The ether extract was then
washed successively with ice-cold 5% NaHCO3 solution
and brine and then dried (Na2SO4) and concentrated. The
crude compound thus obtained was purified by column
chromatography (Silica gel/benzene–pet ether, 1:9)
Yellow oil (2.7 g, 60%); (bp 148–150 8C/1 mm Hg); IR
(CHCl3): n 1666, 1727 cm21; 1H NMR (CDCl3, 200 MHz)
d 1.22 (t, 3H, J¼7.0 Hz, methyl protons), 1.86 (s, 3H,
methyl protons), 2.20–2.57 (m, 8H), 3.24 (brt, 1H,
J¼4.7 Hz), 4.24 (q, 2H, J¼7.0 Hz, methylene protons),
6.27 (d, 1H, J¼1.1 Hz, furan b proton), 7.21(brs, 1H, furan
a proton), 7.33 (brs, 1H, furan a proton); 13C NMR (CDCl3,
50 MHz) d 14.27, 18.14, 23.35, 25.49, 25.98, 34.25, 47.60,
61.27, 111.13, 124.38, 137.60, 139.20, 142.47, 150.67,
172.06, 197.25; MS (EI, 70 eV) m/z 276 (Mþ), 261(M215),
203 (M2CO2Et), 135, 95, 81. Anal. calcd for C16H20O4: C,
69.55; H, 7.30. Found: C, 69.78; H, 7.18.
Colourless oil (25 mg, 38%); IR (CHCl3): n 1735 cm21; 1H
NMR (CDCl3, 200 MHz) d 0.96 (s, 3H, gem-dimethyl
protons), 0.92 (s, 3H, gem-dimethyl protons), 1.17 (s, 3H,
angular methyl protons), 1.22–2.15 (m, 9H), 2.69–2.85 (m,

2810
S. K. Mal et al. / Tetrahedron 60 (2004) 2805–2811
3.1.10. 2-(2-Furan-3-yl-ethyl)-3-methyl-cyclohex-2-
enone (1). A solution of KOH (1.62 g, 28.92 mmol) in
8 mL water and 8 mL ethanol was added to the ketoester
(11) (2 g, 7.25 mmol). The reaction mixture was refluxed
with stirring under N2 atmosphere for 8 h. Excess alcohol
was then removed by distillation under reduced pressure and
the residue was diluted with ice water, acidified with 6 N
HCl, and extracted with ether (4£50 mL). The ether extract
was washed successively with brine solution, 5% NaHCO3
solution, and water and then dried (Na2SO4). Removal of
the solvent gave the title compound, which was purified by
column chromatography.
3H), 1.04 (s, 3H), 1.15–1.41 (m, 4H), 1.45–2.12 (m, 6H),
2.41–2.44 (m, 2H), 6.14 (brs,1H), 7.22 (brs, 1H); MS (EI,
70 eV) m/z 204 (Mþ). Anal. calcd for C14H20O: C, 82.30; H,
9.87. Found: C, 82.56; H, 10.13.
3.1.13. 6,9a-Dimethyl-4,5,7,8,9,9a-hexahydro-
naphtho[1,2-b]furan (23). To a stirred solution of 1
(0.1 g, 0.49 mmol) in ether at 230 8C in N2 atmosphere
add MeLi in ether (1.3 M) (0.35 mL, 0.45 mmol) solution
into the reaction mixture. Stirring was continued for 2 h at
that temperature, and then allowed reaching the rt. Quench
with ice cold NH4Cl solution and extracting with ether
(3£25 mL), washed with ice water and dried (Na2SO4).
Solvent was removed and chromatographed on silica gel
(elution with pet ether).
Light orange oil (0.79 g, 54%); IR (CHCl3): n 1662 cm21
1H NMR (CDCl3, 200 MHz) d 1.84 (s, 3H), 1.88–2.03 (m,
2H), 2.29–2.54 (m, 8H), 6.28 (brs, 1H), 7.18 (brs, 1H), 7.32
(brs, 1H); 13C NMR (CDCl3, 50 MHz) d 21.19, 22.22,
23.98, 26.05, 32.82, 37.83, 111.18, 126.29, 134.77, 138.85,
142.49, 156.04, 198.63; MS (EI, 70 eV) m/z 204 (Mþ), 161,
110, 108, 95, 81. Anal. calcd for C13H16O2: C, 76.44; H,
7.90. Found: C, 76.79; H, 7.75.
Light yellow oil (48 mg, 48%); IR (CHCl3): 1540, 1497,
1367, 1263, 1110, 715 cm21; 1H NMR (CDCl3, 200 MHz) d
1.33 (s, 3H, methyl protons), 1.72 (s, 3H, methyl protons),
1.98–2.12 (m, 4H), 2.25–2.45 (m, 4H), 2.70–2.73 (m, 2H),
6.14 (d, 1H, J¼1.7 Hz, furan b proton), 7.22 (d, 1H,
J¼1.7 Hz, furan a proton); 13C NMR (CDCl3, 50 MHz) d
18.32 (CH2), 19.18 (CH3), 22.96 (CH2), 23.91 (CH2), 25.71
(CH3), 32.13 (CH2), 34.08 (CH2), 36.71, 109.87, 114.77,
126.60, 132.83, 140.45, 158.27; MS (EI, 70 eV) m/z 202
(Mþ), 187, 172, 159, 131, 119, 105, 91, 81. Anal. calcd for
C14H18O: C, 83.12; H, 8.97. Found: C, 83.13; H, 8.82.
3.1.11. 6,6-Dimethyl-4,5,5a,6,7,8-hexahydro-
naphtho[1,2-b]furan (21). To a stirred suspension of CuI
(1.12 g, 5.87 mmol) in dry ether (5 mL) under N2 at 225 8C
(bath temperature) was added MeLi in ether (1.3 M)
(8.95 mL, 11.81 mmol). The resulting yellow suspension
was cooled to 250 8C and BF3:Et2O (0.74 mL, 5.86 mmol)
was added. After 20 min the cyclohexanone (0.4 g,
1.96 mmol) in Et2O (2 mL) was added dropwise (15 min)
and the mixture was stirred at 230 8C for 15 min. An
additional lot of BF3:Et2O (0.74 mL, 5.86 mmol) was added
and stirring was continued at 230 8C for 1 h and then
allowed to 0 8C. Quench it with aqueous NH4Cl and
extracted with ether (4£50 mL). The ether extract was
washed successively with ice water and then dried
(Na2SO4). Removal of the solvent gave the title compound,
which was purified by column chromatography (silica gel,
pet ether).
Acknowledgements
Financial support from DST (New Delhi) and CSIR (New
Delhi) (for fellowship to S.M.) is gratefully acknowledged.
References and notes
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S. K. Mal et al. / Tetrahedron 60 (2004) 2805–2811
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