Total syntheses of the sesquiterpenoids (+)-trans-dracunculifoliol and (+)-4-hydroxyoppositan-7-one

Article abstract of DOI:10.1016/j.tet.2005.01.089

Sesquiterpenoids (+)-trans-dracuncuflifoliol (1) and (+)-4- hydroxyoppositan-7-one (2) were prepared stereoselectively from enantiomerically pure (7aR)-7a-methyl-1,2,5,6,7,7a-hexahydro-4H-inden-4-one ((-)-6), whose synthesis was described herein. Conjugat

Full text of DOI:10.1016/j.tet.2005.01.089

Tetrahedron 61 (2005) 2761–2766
Total syntheses of the sesquiterpenoids (C)-trans-dracunculifoliol
and (C)-4-hydroxyoppositan-7-one
*
Renata M. Oballa, Rebekah Carson, Susan Lait, Jay A. Cadieux and Joel Robichaud
¨
Department of Medicinal Chemistry, Merck Frosst Centre for Therapeutic Research, 16711 TransCanada Highway, Kirkland,
Que., Canada H9H 3L1
Received 2 December 2004; revised 21 January 2005; accepted 21 January 2005
Abstract—Sesquiterpenoids (C)-trans-dracuncuflifoliol (1) and (C)-4-hydroxyoppositan-7-one (2) were prepared stereoselectively from
enantiomerically pure (7aR)-7a-methyl-1,2,5,6,7,7a-hexahydro-4H-inden-4-one ((K)-6), whose synthesis was described herein. Conjugate
addition of the organocopper (I) reagent 10 to (K)-6, followed by epimerization of the ring junction, generated 3 of the 4 contiguous chiral
centers of both natural products.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
The sesquiterpenoid (C)-trans-dracunculifoliol (1) was
isolated from Vassoura oil and was previously synthesized
as a racemate in eighteen linear steps with an overall yield
of 1.8%.1 A structurally related natural product, (C)-4-
hydroxyoppositan-7-one (2) was isolated from the liver-
worts Chiloscyphus pallescens2 and C. rivularis3 and has
not yet been synthesized. While the absolute stereo-
chemistry of either 1 or 2 has not been reported, the natural
product chiloscyphone (3), isolated from C. polyanthus, was
elucidated by an X-ray crystallographic study.4 One of the
goals of this synthetic study is to determine if the absolute
stereochemistry of 1 and 2 is as shown in Scheme 1.
Scheme 1.
Natural products 1 and 2 share a common trans-fused
[4.3.0] bicyclo skeleton and it was envisaged that three of
predominant cis-fused ring junction is obtained.6 However,
the four contiguous chiral centres could be created by the
equilibration of structurally related compounds generally
conjugate addition of an organocopper (I) reagent to enone
dictates that the cis-fused isomer can be equilibrated with
base to produce a mixture of epimers in which the trans-
fused isomer, the thermodynamically more stable of the two
epimers, predominates.7
(K)-6, to generate 5 which, after epimerization of the centre
alpha to the carbonyl, gives the common intermediate 4
(Scheme 1). The stereochemical outcome of the key
conjugate addition reaction was predicted to parallel those
obtained in the previously reported 1,4-addition reactions to
bicyclo[4.3.0]non-9-en-2-ones.5,6 Conjugate addition of
organocoper (I) reagents to enones of general structure 6
proceeds stereoselectively, with the group being introduced
trans to the angular methyl group (i.e., 5). In addition, a
2. Results and discussion
2.1. Synthesis of chiral enone (K)-6
Ohkubo et al.8 reported an enantioselective synthesis of
(C)-6, but the route is laborious (8 steps from a non-
commercial starting material) with an overall yield of 38%.
Keywords: Natural product synthesis; Sesquiterpenoids.
* Corresponding author. Tel.: C1 514 428 3617; fax: C1 514 428 4900;
e-mail: renata_oballa@merck.com
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.01.089

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R. M. Oballa et al. / Tetrahedron 61 (2005) 2761–2766
The synthesis of the chiral enone (K)-6 was readily
accomplished via the route outlined in Scheme 2. The
racemic enone 69 was resolved by condensation with the
anion of (C)-(S)-N,S-dimethyl-S-phenylsulfoximine.10
These conditions delivered a readily separable mixture of
diastereomers 7 (39%) and 8 (50%). Sulfoximine-mediated
resolution of ketones is ideally suited for bicyclic enones
which exhibit diastereoface specificity towards the addition
of the anion of (C)-(S)-N,S-dimethyl-S-phenylsulfoximine.
Lastly, thermolysis of 8 regenerated the sulfoximine and the
optically pure (K)-6. The absolute stereochemistry was
assigned based on the comparison of the sign of rotation to
that of the reported (C)-6,8 in which the absolute
stereochemistry is known.
versa (Scheme 3) and this confirmed the cis-fused nature of
the ring junction. Irradiation of the signal due to H-9 caused
an enhancement of the signal for H-1, thereby verifying that
reagent 10 had introduced the vinyl group trans to the
angular methyl group (Me-10), as predicted.
A trans-fused ring junction was required for the synthesis of
natural products 1 and 2. According to previous studies5,6
and results reported by Dana and co-workers,7 epimeriza-
tion of 5 should lead to a mixture of compounds in which the
trans-fused epimer 4 is thermodynamically favored. In fact,
treatment of 5 with NaOMe in MeOH at 55 8C resulted in a
33:1 mixture of epimers 4 and 5 (Scheme 3). These two
epimers were readily separated by flash chromatography on
silica gel, and the desired synthetic intermediate 4 was
obtained in 93% yield.
2.3. Synthesis of (C)-trans-dracunculifoliol (1)
Elaboration of intermediate 4 to (C)-trans-dracunculifoliol
(1) involved ozonolysis of the exocyclic alkene to afford,
after treatment with triphenylphosphine, the diketone 11
(Scheme 4). A regioselective Wittig reaction was then
attempted and complete selectivity was obtained to generate
the desired keto alkene 12 in 58% yield. This regioselective
Wittig reaction on the sterically less hindered ketone
eliminated the need for a protection/deprotection strategy.
Interestingly, even when 1.5 equiv of ylide were used, no
bis-olefinated product was detected. Reduction of 12 with
Super Hydridew afforded a mixture of 1 and epi-1 in a 3:1
Scheme 2. (a) (S)-(C)-PhS(O)(NMe)CH3, n-BuLi, THF, K78 8C;
(b) toluene, 110–120 8C.
1
ratio.12 The H NMR and 13C NMR data derived from the
synthetic 1 are identical with those of the natural product 1.1
The absolute configuration of the natural product was
confirmed by the fact that the sign of the specific optical
rotation of the synthetic material ([a]20DZC54.4 (c 0.8,
CHCl3)) is the same as that reported for the natural product
([a]20DZC19 (c 0.4, CHCl3), 85% pure by GC1). Thus, the
synthesis of 1 was accomplished in a concise (5 steps) and
enantioselective manner. The overall yield of 1 from (K)-6
was 24%.
2.2. Synthesis of keto-alkene 4
For the synthesis of the key intermediate 4, the stereo-
selective conjugate addition of the organocopper (I) reagent
10 to the bicyclic enone (K)-6 was required (Scheme 3).
Reagent 10 was prepared by sequential treatment of 911 with
t-BuLi and LiCl/CuCN. The conjugate addition of reagent
10 to the bicyclic enone (K)-6 in the presence of TMSBr
provided, after hydrolysis of the resultant silyl enol ether,
one single diastereomer 5 in 82% yield. It was gratifying to
find that the conjugate addition had proceeded stereo-
selectively, as expected (vide supra). The relative configur-
1
ation of 5 was confirmed by the following H NMR nOe
difference experiments. Irradiation of the signal due to
Me-10 caused an enhancement of the signal for H-1 and vice
Scheme 4. (a) O3, CH2Cl2, K78 8C; PPh3, rt; (b) Ph3PCH3Br, n-BuLi,
THF, 0 8C; (c) LiEt3BH, THF, K78 8C to rt.
2.4. Synthesis of (C)-4-hydroxyoppositan-7-one (2)
Elaboration to (C)-4-hydroxyoppositan-7-one (2) required
the formation of a quaternary center at C-2. The first attempt
involved the addition of a methyl group to the ketone of the
Scheme 3. (a) t-BuLi, THF, K78 8C; LiCl/CuCN. (b) TMSBr, THF,
K78 8C; H2O, NH4OH–NH4Cl. (c) NaOMe, MeOH, 55 8C.

R. M. Oballa et al. / Tetrahedron 61 (2005) 2761–2766
2763
natural product was confirmed by the fact that the sign of the
specific optical rotation of the synthetic material
([a]20DZC73.6 (c 0.65, CHCl3)) is the same as that
reported for the natural product ([a]20DZC76.1 (c 0.28,
CHCl3)2).
3. Conclusion
The work described in this paper culminated in the first total
synthesis of (C)-4-hydroxyoppositan-7-one (2) and the first
enantiopure synthesis of (C)-trans-dracunculifoliol (1).
These syntheses started with the enantiomerically pure
bicyclic enone (K)-6, whose efficient synthesis is described
herein. The key step used to generate the advanced common
intermediate 4 involved a stereoselective conjugate addition
of the organocopper (I) reagent 10 to enone (K)-6, followed
by equilibration of the ring junction to the thermodynami-
cally more stable trans-fused isomer 4. This sequence
efficiently generated 3 of the 4 contiguous chiral centers
required in the natural products. Intermediate 4 was
elaborated in a straightforward manner to the keto alkene
12 which was then used to complete the syntheses of both
natural products 1 and 2. The absolute stereochemistries of 1
and 2 were also confirmed by these syntheses.
Scheme 5. (a) MeMgBr, TMSBr, Et2O, K78 to 0 8C; (b) MAD, MeLi,
PhMe, K78 to K25 8C; (c) m-CPBA, CH2Cl2, 0 8C.
model compound 13 (Scheme 5). Reaction of 13 with
MeMgBr provided the tertiary alcohol 14 in 55% yield with
exclusively one stereoisomer at C-2. The following 1H
NMR nOe difference experiments confirmed that the methyl
group added from the less sterically hindered face of the
molecule to provide the undesired stereochemistry at C-2
(axial OH). Irradiation of the signal due to Me-11 caused an
enhancement of the signal for the tertiary alcohol proton
(Scheme 5) and irradiation of the signal due to the newly
introduced Me-10 caused an enhancement of the signal for
H-1, thereby verifying that the Grignard reagent had
delivered the methyl group trans to the axial angular methyl
group (Me-11). Even treatment with MAD (methyl
aluminum-bis-(2,6-di-tert-butyl-4-methylphenoxide)), a
Lewis acid known to complex with the less hindered face
of carbonyls, gave exclusively 14 upon addition of MeLi.
4. Experimental
4.1. General
All substrates and reagents were obtained commercially and
used without further purification unless otherwise noted. All
glassware was dried in an oven overnight and flame dried
under dry nitrogen. Reactions were carried out with
continuous stirring under a positive pressure of nitrogen
except where noted. Flash chromatography was carried out
with silica gel 60, 230–400 mesh. Anhydrous solvents were
purchased from Aldrich and used without further purifi-
cation. TSMBr was distilled from CaH2 immediately before
use and LiCl was flame dried under vacuum. Proton (1H
NMR) and carbon (13C NMR) magnetic resonance spectra
were recorded on a Bruker AMX spectrometer at 300 and
75.3 MHz, respectively, unless otherwise noted. All spectra
were recorded in CDCl3 using residual solvent (CHCl3) as
internal standard. Signal multiplicity was designated
according to the following abbreviations: sZsinglet, dZ
doublet, ddZdoublet of doublets, dddZdoublet of doublet
of doublets, tZtriplet, qZquartet, dtZdoublet of triplets,
dqZdoublet of quartets, mZmultiplet, br sZbroad singlet,
br dZbroad doublet. Elemental analyses were provided by
Oneida Research Services Inc., Whitesboro, NY. High
resolution mass spectra (HRMS-FABC) were obtained at
the Biomedical Mass Spectrometry Unit, McGill
University, Montreal, Quebec, Canada. Rotations were
measured on a Perkin Elmer polarimeter (model #241).
Knowing that the face opposite to the angular axial methyl
group is more accessible, we decided to add the equatorial
alcohol functionality of 2 to the alkene of 12 from the less
hindered face. This transformation firstly required the
epoxidation of 12 with m-CPBA which did, indeed, provide
the desired epoxide 15 in which the stereochemistry was
confirmed by the following 1H NMR nOe difference
experiments (Scheme 5). Irradiation of the signal due to
Me-11 caused an enhancement of the signals for H-9 and the
epoxide protons on C-10 and vice versa.
The reductive opening of the epoxide 15 was accomplished
with LiEt3BH to generate the desired tertiary alcohol with
concomitant reduction of the ketone to provide the diol 16 in
91% yield (Scheme 6). The secondary alcohol of 16 was
oxidized to the ketone with TPAP, thereby completing the
first total synthesis of (C)-4-hydroxyoppositan-7-one (2) in
7 steps and 25% overall yield from (K)-6. The 1H NMR and
13C NMR data derived from the synthetic 2 are identical
with those of natural 2.2 The absolute configuration of the
4.1.1. (4S,7aR)-7a-Methyl-4-[(N-methyl-S-phenylsul-
fonimidoyl)methyl]-2,4,5,6,7,7a-hexahydro-1H-inden-4-
ol (8). To a cold (K30 8C) solution of (C)-(S)-N,S-
dimethyl-S-phenylsulfoximine
93.3 mmol, 2 equiv) in dry THF (230 mL) was slowly
added n-butyllithium (37.3 mL, 2.5 M in hexanes,
(13.6 mL,
15.8 g,
Scheme 6. (a) LiEt3BH, THF, rt; (b) TPAP, NMO, 4A mol. sieves,
CH2Cl2, rt.

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R. M. Oballa et al. / Tetrahedron 61 (2005) 2761–2766
93.3 mmol, 2 equiv). The reaction was then warmed to
room temperature and stirred for 15 min. Once formation of
the sulfoximine ylide was complete, the mixture was cooled
to K78 8C and a solution of 6-methylbicyclo[4.3.0]non-9-
en-2-one (rac-6)9 (7.0 g, 47 mmol, 1 equiv) in THF (50 mL)
was added via cannula, rinsing with THF (2!5 mL). The
reaction was allowed to stir at K78 8C for 1 h, then poured
into a 1:2 mixture of aqueous saturated ammonium chloride
and diethyl ether (200 mL). The aqueous phase was
extracted with diethyl ether (4!200 mL) and the combined
organic extracts were washed with brine (150 mL) and dried
over sodium sulfate. Gradient flash chromatography of the
crude residue (90/10/80/20 hexane/ethyl acetate)
afforded, in order of elution, diastereomers 8 (7.1 g, 47 or
50% yield based on recovered starting material) and 7
(5.4 g, 36 or 39% yield based on recovered starting
material).
34 mmol, 3.9 equiv). This was immediately followed by the
addition of a solution of (K)-6 (1.3 g, 8.8 mmol, 1 equiv) in
THF (10 mL), via cannula. The orange solution was stirred
at K78 8C for 4 h followed by quenching with aqueous HCl
(1%, 200 mL). After warming to room temperature, the
mixture was poured into diethyl ether (400 mL) and sat. aq.
NH4Cl/NH4OH (pH 8, 400 mL) and stirred vigorously
overnight. The deep blue aqueous phase was extracted with
diethyl ether (4!150 mL) and the combined organic
extracts were washed with water (2!150 mL) and brine
(200 mL), then dried over MgSO4. Upon concentration, the
residual oil was subjected to flash column chromatography
(95/5 hexane/ethyl acetate) to yield 5 (1.4 g, 70% yield or
82% based on recovered starting material) followed by
1
recovered starting material (K)-6 (190 mg). H NMR: d
4.91 (1H, s), 4.84 (1H, s), 3.07 (1H, dt, JZ10.9, 7.3 Hz),
2.59 (1H, d, JZ10.6 Hz), 2.11–2.28 (3H, m), 1.97–2.08
(1H, m), 1.85–1.93 (1H, m), 1.65–1.84 (4H, m), 1.45–1.54
(2H, m, 5d), 1.12 (3H, s), 0.98 (6H, dd, JZ12.4, 6.8 Hz);
13C NMR (100.4 MHz): d 213.9, 156.9, 106.0, 62.7, 47.2,
46.2, 41.2, 39.4, 34.8, 33.6, 29.4, 29.0, 23.0, 21.4, 20.8.
Compound 8. [a]20DZC21.5 (c 1.185, CHCl3); 1H NMR: d
7.87 (2H, d), 7.58 (3H, m), 5.83 (1H, br s), 3.38 (2H, q), 2.65
(3H, s), 2.19 (2H, m), 1.20–1.75 (9H, m), 0.80 (3H, s); 13C
NMR: d 150.9, 138.2, 133.0, 129.3, 129.2, 128.8, 125.7,
72.8, 62.2, 46.2, 43.9, 40.7, 39.5, 31.4, 28.6, 24.4, 22.4,
20.7; HRMS (FABC) m/z Calcd for C18H25NO2S
320.1606, found: 320.1685. Anal. Calcd for C18H25NO2S:
C, 67.67; H, 7.89; N, 4.38, found: C, 67.64; H, 7.51; N, 4.33.
4.1.5. (3S,3aR,7aR)-3-(1-Isopropylvinyl)-7a-methylocta-
hydro-4H-inden-4-one (4). A solution of 5 (0.8 g,
3.5 mmol, 1 equiv) and NaOMe (6 mL, 0.5 M in MeOH,
3 mmol, 0.9 equiv) was stirred for 1 week at 55 8C. The
reaction was quenched with 30 mL of water, and the
residual methanol was removed by rotary evaporation.
Diethyl ether (60 mL) and sat. aq. NaHCO3 (60 mL) were
added and the aqueous phase was extracted with diethyl
ether (4!60 mL). The combined organic extracts were
washed with sat. aq. NaHCO3 (125 mL), brine (125 mL)
4.1.2. (4R,7aS)-7a-Methyl-4-[(N-methyl-S-phenylsul-
fonimidoyl)methyl]-2,4,5,6,7,7a-hexahydro-1H-inden-4-
1
ol (7). [a]20DZC36.3 (c 1.075, CHCl3); H NMR: d 7.81
(2H, d), 7.62 (3H, m), 5.87 (1H, br s), 3.35 (2H, br s), 2.61
(3H, s), 2.20–2.45 (2H, m), 1.20–1.85 (9H, m), 0.98 (3H, s).
13C NMR: d 149.4, 138.9, 132.9, 129.3, 128.9, 128.8, 126.4,
72.1, 62.7, 60.2, 46.4, 43.6, 41.5, 40.9, 28.8, 28.7, 24.1,
20.0; HRMS (FABC) m/z Calcd for C18H25NO2S
320.1606, found: 320.1685. Anal. Calcd for C18H25NO2S:
C, 67.67; H, 7.89; N, 4.38, found: C, 67.10; H, 7.70; N, 4.32.
1
and dried over MgSO4. The H NMR ratio of the crude
material indicated a 33:1 ratio of epimers 4 and 5. The
mixture was subjected to flash column chromatography
(gradiant elution of 95/5/90/10 hexane/ethyl acetate) to
yield 4 (0.72 g, 93% yield). [a]20DZC53.4 (c 0.825,
CHCl3); 1H NMR: d 4.70 (1H, s), 4.58 (1H, s), 2.83 (1H, dt,
JZ10.9, 6.6 Hz), 2.56 (1H, d, JZ11.1 Hz), 2.21–2.32 (3H,
m), 1.75–2.13 (4H, m), 1.51–1.69 (3H, m), 1.36–1.47 (1H,
m), 1.03 (6H, dd, JZ6.8, 5.5 Hz), 0.74 (3H, s); 13C NMR: d
210.5, 160.0, 104.1, 64.8, 49.1, 41.4, 39.9, 39.2, 38.5, 33.5,
29.6, 24.2, 22.4, 18.5; HRMS (FABC) m/z Calcd for
C15H24O 221.1827, found: 221.1904. Anal. Calcd for
C15H24O: C, 81.76; H, 10.98; found: C, 81.04; H, 10.40.
4.1.3. (7aR)-7a-Methyl-1,2,5,6,7,7a-hexahydro-4H-
inden-4-one ((K)-6). A solution of 8 (10.1 g, 31.6 mmol,
1 equiv) in toluene (200 mL) was refluxed overnight (oil
bath temperature 110–120 8C). Since it was difficult to
remove the toluene by rotary evaporation without also
evaporating the product (K)-6, the reaction mixture was
loaded directly onto a silica gel column and flushed with
hexane to elute the toluene. This was followed by gradient
elution (100/0/90/10 hexane/diethyl ether) to afford
(K)-6 (3.7 g, 79% yield). [a]20DZK114.5 (c 1.135,
4.1.6. (3S,3aR,7aR)-3-Isobutyryl-7a-methyloctahydro-
4H-inden-4-one (11). A solution of 4 (0.7 g, 3.3 mmol,
1 equiv) in CH2Cl2 (73 mL) was cooled to K78 8C. O3 was
bubbled through the solution until it turned pale blue in
colour (5–10 min). N2 was then bubbled through the
solution to remove the excess O3, rendering the reaction
mixture colourless. Triphenylphosphine (1.8 g, 6.8 mmol,
2.1 equiv) was added and the mixture was allowed to warm
to room temperature. The reaction was stirred for 3 h,
followed by removal of the solvent by rotary evaporation.
The crude mixture was flash chromatographed (gradient
elution of 95/5/90/10 hexane/ethyl acetate) to afford
the diketone 11 (0.6 g, 84% yield), a colourless oil.
1
CHCl3). H NMR identical to that reported for rac-6.9 In
order to recover the (C)-(S)-N,S-dimethyl-S-phenylsul-
foximine, the column was eluted with ethyl acetate/acetone
(50/50) to afford the sulfoximine (3.6 g, 90% recovery) in an
unchanged state of optical purity.
4.1.4. (3S,3aS,7aR)-3-(1-Isopropylvinyl)-7a-methylocta-
hydro-4H-inden-4-one (5). To a cold (K78 8C), yellow
solution of t-butyllithium (1.7 M in pentane, 31 mL,
53 mmol, 6 equiv) in THF (200 mL) was slowly added
2-bromo-3-methylbut-1-ene (9)11 (4.0 g, 27 mmol, 3 equiv)
in THF (50 mL) over 30 min. To the resultant clear, cold
(K78 8C) solution was added, via cannula, a solution of
LiCl (2.3 g, 53 mmol, 6 equiv) and CuCN (2.6 g, 29 mmol,
3.2 equiv) in THF (80 mL) followed by TMSBr (4.5 mL,
1
[a]20DZC58.8 (c 0.585, CHCl3); H NMR: d 3.35 (1H,
dt, JZ10.5, 5.7 Hz), 2.83 (1H, d, JZ10.7 Hz), 2.76 (1H,
septet, JZ6.9 Hz), 2.24 (2H, m), 1.80–2.06 (4H, m), 1.52–
1.71 (4H, m), 1.09 (6H, t, JZ7.2 Hz), 0.73 (3H, s); 13C

R. M. Oballa et al. / Tetrahedron 61 (2005) 2761–2766
2765
NMR: d 209.5, 216.8, 62.6, 48.7, 44.0, 41.0, 40.5, 39.8,
37.6, 26.1, 23.7, 18.4, 17.9, 17.8; HRMS (FABC) m/z
Calcd for C14H22O 223.1620, found: 223.1697. Anal. Calcd
for C14H22O: C, 75.63; H, 9.97; found: C, 75.03; H, 9.30.
223.2063. Anal. Calcd for C15H26O: C, 81.02; H, 11.79;
found: C, 81.94; H, 12.20.
Compound epi-1. [a]20DZC49.4 (c 0.32, CHCl3); 1H NMR
(400 MHz): d 4.76 (1H, d, JZ1.5 Hz), 4.39 (1H, d, JZ
1.6 Hz), 3.36 (1H, d, JZ7.9 Hz), 2.24 (2H, dq, JZ9.4,
1.7 Hz), 1.97 (1H, d, JZ11.7 Hz), 1.91 (1H, dt, JZ13.1,
6.0 Hz),1.48–1.69 (7H, m), 1.21–1.35 (3H, m), 0.97 (3H, d,
JZ6.6 Hz), 0.90 (3H, d, JZ6.7 Hz), 0.64 (3H, s); 13C
NMR: d 148.5, 104.3, 54.1, 44.1, 39.5, 39.2, 38.5, 36.2,
33.3, 23.9, 19.9, 19.5, 19.2, 17.8; HRMS (FABC) m/z
Calcd for C15H26O 223.1984, found: 223.2024. Anal. Calcd
for C15H26O: C, 81.02; H, 11.79; found: C, 81.01; H, 12.16.
4.1.7. 2-Methyl-1-[(1S,3aR,7aS)-3a-methyl-7-methylene-
octahydro-1H-inden-1-yl]propan-1-one (12). To a cold
(0 8C), stirred solution of bromomethyltriphenylphosphine
(0.36 g, 1.0 mmol, 1 equiv) in THF (5.7 mL) was added
dropwise n-BuLi (2.5 M in hexanes, 0.4 mL, 1.0 mmol,
1 equiv). The resultant bright yellow solution was stirred at
0 8C for 45 min, followed by the addition of a solution of
diketone 11 (0.23 g, 1.0 mmol, 1 equiv) in THF (6 mL). The
reaction mixture was allowed to warm slowly to room
temperature for 1 h. At this time another 0.25 equiv of ylide
was prepared using the above procedure. Since all the
starting material had not been consumed after 1 h, the
0.25 equiv of prepared ylide was added to the reaction
mixture. After an additional h, the reaction was quenched
with sat. aq. NH4Cl (25 mL). The aqueous phase was
extracted with diethyl ether (4!40 mL) and the combined
organic extracts were washed with brine (3!40 mL) and
then dried over MgSO4. After removal of the solvent by
rotary evaporation, the crude mixture was flash chromato-
graphed (gradient elution of 95/5/90/10 hexane/diethyl
ether) to afford product 12 (0.13 g, 58% yield). [a]20DZ
C100.7 (c 3.1, CHCl3); 1H NMR: d 4.68 (1H, s), 4.31 (1H,
s), 3.08 (1H, dt, JZ11.2, 6.3 Hz), 2.71 (1H, septet, JZ
6.9 Hz), 2.35 (1H, d, JZ11.3 Hz), 2.22 (1H, ddd, JZ13.5,
2.9, 1.5 Hz), 1.89–2.10 (2H, m), 1.30–1.78 (7H, m), 1.07
(6H, dd, JZ6.9, 3.0 Hz), 0.65 (3H, s); 13C NMR: d 217.2,
147.8, 104.8, 55.5, 47.5, 44.1, 40.4, 39.4, 38.8, 35.3, 26.5,
23.3, 18.3, 18.3, 17.9; HRMS (FABC) m/z Calcd for
C15H24O 221.1827, found: 221.1904. Anal. Calcd for
C15H24O: C, 81.76; H, 10.98; found: C, 81.30; H, 10.85.
4.1.9. (3S,3aR,7aR)-3-Isopropenyl-7a-methyloctahydro-
4H-inden-4-one (13). Synthesized as reported by Piers and
Boulet.13
4.1.10. (3S,3aR,4S,7aR)-3-Isopropenyl-4,7a-dimethyl-
octahydro-1H-inden-4-ol (14). To a cold (K78 8C), stirred
solution of MeMgBr (1.4 M in 3:1 toluene:THF, 1.1 mL,
1.5 mmol, 9 equiv) in diethyl ether (2 mL) was added, via
cannula, a solution of 13 (32.3 mg, 0.17 mmol) and TMSBr
(100 ml, 0.76 mmol, 4.5 equiv) in diethyl ether (1 mL). The
mixture was stirred at K78 8C for 30 min, K43 8C for 3 h
then 0 8C for 2 h. The reaction was quenched with water
(1 mL) and treated with aqueous HCl (10%, 0.5 mL) for 1 h
at room temperature. Water (10 mL) was added and the
product was extracted with diethyl ether (3!5 mL). The
combined organic extracts were washed with brine (10 mL)
and dried over MgSO4. After rotary evaporation of solvents,
the product was flash chromatographed over silica (95/5
1
hexane/ethyl acetate) to yield 14 (19.5 mg, 55% yield). H
NMR (500 MHz): d 4.82 (1H, s), 4.63 (1H, s), 2.80 (1H, dt,
JZ11.4, 5.5 Hz), 1.89–1.98 (1H, m), 1.78 (1H, tq, JZ13.7,
3.9 Hz), 1.69 (4H, br s), 1.59 (1H, br d, JZ14.1 Hz), 1.45
(1H, br d, JZ13.9 Hz), 1.34–1.40 (2H, m), 1.29 (1H, td, JZ
13.8, 4.8 Hz), 1.26 (1H, d, JZ11.9 Hz), 1.17 (3H, s), 1.08–
1.20 (2H, m), 1.05 (1H, s), 1.02 (3H, s). 13C NMR
(100.4 MHz): d 149.9, 110.8, 72.6, 55.3, 44.1, 42.1, 41.4,
41.2, 39.3, 29.6, 28.0, 19.9, 19.0, 17.7.
4.1.8. 2-Methyl-1-[(1S,3aR,7aS)-3a-methyl-7-methylene-
octahydro-1H-inden-1-yl]propan-1-ol (1). To a cold
(K78 8C), stirred solution of 12 (26 mg, 0.12 mmol,
1 equiv) in THF (1.5 mL) was added Super Hydridew
(1 M in THF, 0.3 mL, 2.5 equiv). The mixture was allowed
to warm to 0 8C and stirred for 1.5 h followed by the
addition of another aliquot of Super Hydridew (1 M in THF,
0.3 mL, 2.5 equiv). The mixture was warmed to rt and
stirred for 1.5 h. Water was added and the product was
extracted with diethyl ether (2!20 mL), washed with brine
(1!10 mL) and dried over MgSO4. After removal of the
solvent by rotary evaporation, the crude mixture was
purified by flash chromatography (90/10 hexane/diethyl
ether) to afford the desired natural product 1 (16.8 mg, 64%
yield) followed by the corresponding diastereomer at C-12,
epi-1 (5.7 mg, 22% yield).
4.1.11. 2-Methyl-1-[(3S,3aR,4R,7aR)-7a-methylocta-
hydrospiro[indene-4,20-oxiran]-3-yl]propan-1-one (15).
To a cold (0 8C), stirred solution of 12 (23 mg,
0.11 mmol, 1 equiv) in CH2Cl2 (2 mL) was added m-chloro-
perbenzoic acid (m-CPBA, 70% pure, 31 mg, 0.13 mmol,
1.2 equiv) and the reaction was allowed to stir at 0 8C for
30 min. The reaction was then warmed to room temperature
and an additional aliquot of m-CPBA (44 mg, 1.7 equiv)
was added and the mixture was stirred for 45 min. Excess
m-CPBA was destroyed by the addition of sat. aq. Na2S2O3
(1 mL). The aqueous layer was extracted with diethyl ether
(2!25 mL) and the combined organic extracts were washed
with sat. aq. NaHCO3 (2!25 mL) and then dried over
MgSO4. After removal of solvents by rotary evaporation,
the residue was flash chromatographed on silica gel (95/5
hexane/ethyl acetate) to yield epoxide 15 (18.5 mg, 75%
Compound 1. [a]20DZC54.4 (c 0.80, CHCl3); natural 1:
[a]20DZC19 (c 0.4, CHCl3) 85% pure by GC.1 1H NMR
(500 MHz): d 4.86 (1H, d, JZ1.3 Hz), 4.71 (1H, d, JZ
1.4 Hz), 3.22 (1H, dd, JZ9.9, 2.4 Hz), 2.27 (1H, dd, JZ
13.0, 4.9 Hz), 2.21 (1H, dq, JZ10.3, 5.0 Hz), 1.96 (1H, dt,
JZ13.0, 5.6 Hz), 1.5–1.86 (8H, m), 1.22–1.35 (3H, m), 0.97
(3H, d, JZ6.9 Hz), 0.88 (3H, d, JZ6.8 Hz), 0.64 (3H, s);
13C NMR: d 151.2, 105.7, 82.9, 58.6, 45.4, 39.4, 39.19,
39.16, 36.6, 31.2, 25.6, 24.0, 20.4, 18.0, 14.6; HRMS
(FABC) m/z Calcd for C15H26O 223.1984, found:
1
yield). [a]20DZC63.2 (c 0.85, CHCl3); H NMR: d 2.80
(1H, br s), 2.66 (1H, dt, JZ11.1, 5.6 Hz), 2.56 (2H, m), 2.26
(1H, d, JZ11.4 Hz), 1.94 (1H, m), 1.47–1.83 (7H, m), 1.22–
1.32 (2H, m), 1.02 (6H, t, JZ7.4 Hz), 0.82 (3H, s); 13C
NMR: d 217.1, 59.2, 54.5, 49.8, 45.5, 45.4, 41.2, 40.1, 37.9,

2766
R. M. Oballa et al. / Tetrahedron 61 (2005) 2761–2766
34.4, 27.2, 22.2, 18.4, 18.0, 17.5; HRMS (FABC) m/z
Calcd for C15H24O2 237.1776, found: 237.1854.
1.31–1.58 (4H, m), 1.13–1.26 (2H, m), 1.09 (9H, s and d),
0.86 (3H, s); 13C NMR: d 220.5, 72.4, 60.6, 46.1, 43.7, 43.6,
42.1, 41.7, 38.5, 27.0, 21.6, 21.3, 20.1, 18.3, 18.1; HRMS
(FAB MCHCNa) m/z Calcd for C15H26O2 261.1833,
found: 261.1830. Anal. Calcd for C15H26O2: C, 75.58; H,
10.99; found: C, 74.93; H, 10.75.
4.1.12. (3S,3aR,4R,7aR)-3-(1-Hydroxy-2-methylpropyl)-
4,7a-dimethyloctahydro-1H-inden-4-ol (16). To a stirred
solution of 15 (16 mg, 0.07 mmol, 1 equiv) in THF (1.5 mL)
was added Super Hydridew (1 M in THF, 0.3 mL, 4 equiv)
and the mixture was stirred at rt for 40 min. An additional
aliquot of Super Hydridew (1 M in THF, 0.3 mL, 4 equiv)
was added and the reaction mixture was stirred for 2 h at rt.
The reaction was then cooled to 0 8C and quenched with
10% HCl (w5 mL). The solution was neutralized with sat.
aq. NaHCO3. The mixture was extracted with ethyl acetate
(3!25 mL) and the combined organic extracts were washed
with brine (1!25 mL) and dried over MgSO4. After rotary
evaporation of solvents, the residue was flash chromato-
graphed on silica gel (gradient elution of 90/10/80/20
hexane/ethyl acetate) to afford the diol 16 (14.7 mg, 91%
References and notes
1. Weyerstahl, P.; Marschall, H.; Schneider, K. Liebigs Ann. Org.
Bioorg. Chem. 1995, 2, 231–240.
2. Harrison, L. J.; Asakawa, Y. Phytochemistry 1991,
3806–3807. In this report, (C)-4-hydroxyoppositan-7-one
(2) is referred to as ent-(5R,6S,9R)-4a-hydroxyoppositan-4-
one.
1
yield) as a white powder. H NMR: d 3.84 (2H, br s), 3.30
3. Wu, C.; Gunatilaka, A. A. L.; McCabe, F. L.; Johnson, R. K.;
Spjut, R. W.; Kingston, D. G. I. J. Nat. Prod. 1997, 60,
1281–1286.
(1H, dd, JZ9.5, 1.7 Hz), 2.04 (1H, m), 1.68–1.91 (3H, m),
1.27–1.62 (8H, m), 1.23 (3H, s), 1.01–1.22 (1H, m), 0.99
(3H, d, JZ6.9 Hz), 0.86 (3H, d, JZ7.0 Hz), 0.85 (3H, s).
4. Tori, M.; Hasebe, T.; Asakawa, Y.; Ogawa, K.; Yoshimura, S.
Bull. Chem. Soc. Jpn. 1991, 64, 2303–2305.
5. Piers, E.; Oballa, R. M. Tetrahedron Lett. 1995, 36,
5857–5860.
4.1.13. 1-[(1S,3aR,7R,7aR)-7-Hydroxy-3a,7-dimethyl-
octahydro-1H-inden-1-yl]-2-methylpropan-1-one (2).
To a stirred mixture of the diol 16 (12.5 mg, 0.05 mmol,
1.0 equiv), 4-methylmorpholine-N-oxide, NMO (9 mg,
6. Piers, E.; Oballa, R. M. J. Org. Chem. 1996, 61, 8439–8447.
7. Cicero, B. L.; Weisbuch, F.; Dana, G. J. Org. Chem. 1981, 46,
914.
˚
0.08 mmol, 1.5 equiv) and powdered 4 A molecular sieves
(20 mg) in CH2Cl2 (1.5 mL) was added tetrapropyl-
ammoniumperruthenate, TPAP (4.6 mg, 0.01 mmol,
0.25 equiv). The reaction was allowed to stir at rt for 3 h.
The reaction mixture was then filtered through a short
column of silica. After rotary evaporation of the solvents,
the residue was flash chromatographed on silica gel (80/20
hexane/ethyl acetate) to yield the desired natural product 2
(12.1 mg, 97% yield). [a]20DZC73.6 (c 0.65, CHCl3);
natural 2: [a]20DZC76.1 (c 0.28, CHCl3)2 and C84 (c
8. Ohkubo, T.; Akino, H.; Asaoka, M.; Takei, H. Tetrahedron
Lett. 1995, 36, 3365–3368.
9. Helquist, P.; Bal, S. A.; Marfat, A. J. Org. Chem. 1982, 47,
5045–5050.
10. Johnson, C. R.; Zeller, J. R. J. Am. Chem. Soc. 1982, 104,
4021–4023.
11. Hara, S.; Dojo, H.; Takinami, S.; Suzuki, A. Tetrahedron Lett.
1983, 24, 731–734.
1
0.31, CHCl3)3; H NMR: d 3.07 (1H, dt, JZ11.4, 5.8 Hz),
12. A 2.5:1 ratio of 1 and epi-1 was obtained from the LiAlH4
reduction of rac-12 as reported in Ref. 1.
2.75 (1H, septet, JZ6.9 Hz), 2.00 (1H, m), 1.86 (1H, d, JZ
11.7 Hz), 1.79 (2H, br d), 1.63 (2H, dd, JZ12.6, 2.5 Hz),
13. Piers, E.; Boulet, S. L. Tetrahedron Lett. 1997, 38, 8815–8818.